16-Fluoro prostaglandins

ABSTRACT

11-Unsubstituted 16-fluoro-prostaglandin E 2  useful as blood pressure lowering agents.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.06/245,289 filed Mar. 19, 1981, now abandoned, which is a continuationof U.S. patent application Ser. No. 06/132,720 filed Mar. 24, 1980, nowabandoned, which in turn is a divisional of U.S. patent application Ser.No. 06/026,126 filed Apr. 2, 1979, now U.S. Pat. No. 4,227,019, which inturn is a divisional of U.S. patent application Ser. No. 780,878 filedMar. 24, 1977, now abandoned, which in turn is a divisional of U.S.patent application Ser. No. 05/614,044 filed Sept. 17, 1975, now U.S.Pat. No. 4,036,871 which in turn is a division of U.S. patentapplication Ser. No. 05/480,458 filed June 18, 1974, now U.S. Pat. No.4,052,446, which in turn is a continuation-in-part of U.S. patentapplication Ser. No. 386,117, Holland, Jernow and Rosen filed Aug. 6,1973 now abandoned. Also related to this application is U.S. patentapplication Ser. No. 300,633, Rosen and Kienzle filed Oct. 25, 1972,U.S. patent application Ser. No. 381,322, Rosen and Kienzle filed July20, 1973 and U.S. patent application Ser. No. 317,589, filed Dec. 22,1972, Jernow and Rosen.

SUMMARY OF THE INVENTION

In accordance with this invention, a process has been discovered forpreparing prostaglandin active compounds of the formula: ##STR1##wherein R is hydrogen or lower alkyl; R₂ is hydroxy; R₃ is hydrogen ortaken together with R₂ to form oxo; R₁ is hydrogen, lower alkyl,carboxy, lower alkoxy carbonyl, --CH₂ OR₈ and ##STR2## R₈ is hydrogen orlower alkyl; R₉ ' is hydrogen; lower alkyl or fluoro; and R₉ is hydrogenor lower alkyl; and the dotted bond can be optionally hydrogenated; froma compound of the formula: ##STR3## wherein R₄ is lower alkyl, hydrogenor --COOR'₁ ; R₁ ' is hydrogen or lower alkyl; R₆ is hydroxy protectedwith a hydrolyzable ether or ester group; and R₉ and R₉ ' are as above.

In accordance with this invention, new and novel prostaglandin compoundsof the formula: ##STR4## wherein R, R₂ and R₃ are as above; R₁ " islower alkyl, hydrogen, carboxy, lower alkoxy carbonyl, --CH₂ OR₈ or##STR5## and R₈, R₉, and R₉ ' are as above; with the proviso that whenR₉ and R₉ ' are all hydrogen, R₁ " is lower alkoxycarbonyl, --CH₂ OR₈ or##STR6## and the dotted bond can be optionally hydrogenated have beenprepared which have cardiovascular activity, induce labor in pregnantfemales; are useful for terminating pregnancies and for combattinggastro-hyperacidity. The compounds of formula I-A are also useful asbronchodilators.

DETAILED DESCRIPTION OF THE INVENTION

As used throughout this application, the term "lower alkyl" includesboth straight chain and branched chain alkyl groups having from 1 to 7carbon atoms, such as methyl, ethyl and propyl, preferably methyl. Asused herein, the term "lower alkoxy" comprehends groups having from 1 to7 carbon atoms such as methoxy and ethoxy. As also used herein, the term"lower alkanoic acids" comprehends an alkanoic acid of 1 to 7 carbonatoms such as formic acid and acetic acid. As further used herein, theterm "halogen" or "halo", unless otherwise stated, comprehends fluorine,chlorine, bromine and iodine.

In the process of this invention, all compounds having one or moreasymmetric carbon atoms can be produced as racemic mixtures. Theseracemic mixtures which are obtained can be resolved at the appropriatesteps in the process of this invention by methods well known in the artdiscussed more fully below, whereupon subsequent products may beobtained as the corresponding optically pure enantiomers.

In the pictorial representation of the compounds given throughout thisapplication, a thickened tapered line ( ) indicates a substituent whichis in the beta-orientation (above the plane of the molecule), a dottedline (---) indicates a substituent which is in the alpha-orientation(below the plane of the molecule) and a wavy line ( ) indicates asubstituent which is in either the alpha- or beta-orientation ormixtures of these isomers. It is to be understood that the pictorialrepresentations of the compounds given throughout the specification areset forth for convenience and are to be construed as inclusive of otherforms including enantiomers and racemates and are not to be construed aslimited to the particular form shown.

As also used herein, the term "aryl" signifies mononuclear aromatichydrocarbon groups such as phenyl, tolyl, etc. which can beunsubstituted or substituted in one or more positions with a loweralkylenedioxy, a halogen, a nitro, a lower alkyl or a lower alkoxysubstituent, and polynuclear aryl groups such as naphthyl, anthryl,phenanthryl, azulyl, etc., which can be substituted with one or more ofthe aforementioned groups. The preferred aryl groups are the substitutedand unsubstituted mononuclear aryl groups, particularly phenyl. The term"aryl lower alkyl" comprehends groups wherein aryl and lower alkyl areas defined above, particularly benzyl. The term "aryl lower alkanoicacid" comprehends acids wherein "aryl" and "lower alkanoic acid" are asdefined above, particularly benzoic acid.

As still further used herein, the term "carboxy protected with a groupconvertible thereto by hydrolysis" comprehends any conventional organicacid protecting group which can be removed by hydrolysis. The preferredorganic acid protecting groups are the esters. Any conventional esterthat can by hydrolyzed to yield the acid can be utilized as theprotecting group. Exemplary esters useful for this purpose are the loweralkyl esters, particularly methyl and ethyl ester, the aryl esters,particularly phenyl ester and the aryl lower alkyl esters, particularlybenzyl ester.

As used herein, the term "hydrolyzable ester or ether group" designatesany ester or ether which can be hydrolyzed to yield the hydroxy group.Exemplary ester groups useful for this purpose are those in which theacyl moiety is derived from a lower alkanoic, an aryl lower alkanoic,phosphoric, carbonic or a lower alkane dicarboxylic acid. Among theacids which can be utilized to form such ester groups are the acidanhydrides and the acid halides, preferably chlorides or bromides, withthe lower alkanoic acid anhydrides, e.g., acetic anhydride and caproicanhydride, the aryl lower alkanoic acid anhydrides, e.g., benzoic acidanhydrides, lower alkane dicarboxylic acid anhydrides, e.g., succinicanhydride, and chloroformates, e.g., trichloroethylchloroformate, beingpreferred. A suitable ether protecting group is, for example, thetetrahydropyranyl ether or 4-methoxy-5,6-dihydro-2H-pyranyl ether.Others are arylmethyl ethers such as benzyl, benzhydryl, or tritylethers or alpha-lower alkoxy lower alkyl ether, for example,methoxymethyl or allylic ethers, or trialkyl silyl ethers such astrimethyl silyl ether or dimethyl-tert-butyl silyl ethers.

Where R₁ " in the compound of formula I-A is --CH₂ OR₈, the preferredcompounds are those where at least one of R₉ or R₉ ' is other thanhydrogen. Where R"₁ in the compound of formula I-A is loweralkoxycarbonyl, the preferred compounds are those where at least one ofR₉ or R₉ ' is other than hydrogen.

The compounds of formula I wherein R₂ and R₃ form an oxo group, i.e.,the compounds of the formula: ##STR7## wherein R, R₁, R₉ and R₉ ' are asabove; and the dotted bond can be optionally hydrogenated; are useful inthe same manner as prostaglandin E₂. The compounds of formula I-B areespecially valuable for preventing hyperacidity in the stomach and forbroncho-dilation. On the other hand, the compounds of formula I-A whereR₂ is hydroxy and R₃ is hydrogen, i.e., the compounds of the formula:##STR8## wherein R, R₁, R₉ and R₉ ' are as above and the dotted bond canbe optionally hydrogenated; are useful in the same manner asprostaglandin F₂ α.

The prostaglandins E₁, E₂ and F₂α have the ability to modify theactivity of the alimentary and reproductive smooth muscles to blockmucous and enzyme secretions by the stomach, to stimulate the synthesisof adrenal corticoids, to modify blood pressure and lipolysis. Since thecompounds of formulae I-B and I-C have prostaglandin E₁, E₂ and F₂αactivity, the compounds of formulae I-B and I-C also possess thesevaluable properties. Furthermore, the compounds of formula I-B and I-Care active in the same manner as these prostaglandins in inducing laborand pregnancy in females and for therapeutically terminating pregnancy.The compounds of formula I-B are useful in the same manner as theprostaglandin E₂ in that they lower blood pressure and inhibit bloodplatelet aggregation. On the other hand, the compounds of formula I-Care blood pressure raising agents in the same manner as prostaglandinF₂α.

That the compounds of formula I-B are effective anti-ulcerogeniccompounds can be seen by the fact that the ED₅₀ of a compound such as7-[3 alphamethyl-5-oxo-2-beta-(3-alpha-hydroxy-4-fluoro-1-trans-octenyl)-1-alphacyclopentyl]-cis-5-heptenoicacid is 0.47 i.p. and 0.0001 p.o. when administered to rats by thefollowing test:

Rats were fasted 16 hours prior to the subcutaneous administration ofIndomethacin at 100 mg/kg. Simultaneously with the Indomethacin dose,the test compounds were administered intraperitoneally at three doselevels and dosed orally at six dose levels. These doses of the testcompounds were repeated every thirty minutes for six hours (12 doses).After six hours, the animals were killed and the stomachs were examinedfor ulceration or hemorrhage. Protection from incidence of ulcerationwas used to determine activity. Five mice were used per dose level andED₅₀ values were calculated.

The compounds of formula I can be used by the pharmaceutical andveterinary arts in a variety of pharmaceutical or veterinarypreparations. In these preparations, the new compounds areadministerable in the form of tablets, pills, powders, capsules,injectables, solutions, suppositories, emulsions, dispersions, feedpre-mixes and in other suitable forms. The pharmaceutical or veterinarypreparations which contain the compound of formula I are convenientlyadmixed with a non-toxic pharmaceutical organic carrier or a non-toxicpharmaceutical inorganic carrier. Typical of pharmaceutically acceptablecarriers are, for example, water, gelatin lactose, starches, magnesiumstearate, talc, vegetable oils, polyalkylene glycols, petroleum jellyand other conventionally employed pharmaceutically acceptable carriers.The pharmaceutical preparations may also contain non-toxic auxiliarysubstances such as emulsifying, preserving and wetting agents and thelike, as for example, sorbitan monolaurate, triethanol amine oleate,polyoxyethylene sorbitan, dioctyl sodium sulfosuccinate and the like.

The daily dose administered for the compounds will of course vary withthe particular novel compounds employed because of the very potency ofthe compounds, the chosen route of administration and the size of therecipient. The dosage administered is not subject to definite bounds butit will usually be in effective amounts of the pharmacologicallyfunction of the prostaglandin. Representative of a typical method foradministering the prostaglandin compounds of formula I is by theinjectable type administration route. By this route, a sterile solutioncontaining the prostaglandin of formula I can be administeredintraveneously at the rate of 0.01 microgram to 0.15 microgram perminute per kilogram of body weight. The compound to be administered bythe injectable route is in a form suitable for injection such as mixedwith a sterile aqueous solution having incorporated therein an agentthat delays adsorption such as aluminum monostereate and the like.

For administering the compounds of formula I to domestic animals orlaboratory animals, the compounds are prepared in the form of a foodpre-mix such as mixing with dried fish meal, oatmeal and the like, andthe prepared pre-mix is added to a regular feed thereby administeringthe compound to the domestic or laboratory animal in the form of a feed.

The compound of formula I-C wherein R₁ is --CH₂ OR₈ and R is hydrogen,i.e., a compound of the formula: ##STR9## wherein R₈, R₉ and R₉ ' are asabove; can be prepared from a compound of the formula: ##STR10## whereinR₆, R₉ and R₉ ' are as above; via the following intermediates: ##STR11##wherein R₆, R₉ and R₉ ' are as above; ##STR12## wherein R₆, R₉ and R₉ 'are as above; and R₆ ' is hydroxy protected by a hydrolyzable ether orester group; or --OR₈ ' and R₈ ' is lower alkyl. ##STR13## wherein R₆,R₆ ', R₉ ' are as above; ##STR14## wherein R₆ ' and R₆ are as above.

The starting material of formula II-A when R₉ and R₉ ' are hydrogen andits method of preparation is disclosed in U.S. patent application Ser.No. 300,633, filed Oct. 25, 1972, Kienzle et al. (please note formulaXXI-C and Example 20 in Ser. No. 300,633). The compound of formula II-Ais converted to the compound of formula III by treating the compound offormula II-A with borane. In carrying out this reaction, temperature andpressure are not critical and the reaction can be carried out at roomtemperature and atmospheric pressure. On the other hand, elevated orlower temperatures can be utilized. Generally, it is preferred to carryout this reaction at a temperature of from -20° C. to +50° C. Thisreaction is generally carried out in the presence of an inert organicsolvent. In carrying out this reaction, any conventional inert organicsolvent can be utilized. Among the preferred solvents are the ethersolvents such as diethyl ether, tetrahydrofruan, dioxane, etc.

The compound of formula III is converted to the compound of formula IVby either esterifying or etherifying the free hydroxy group. Anyconventional method of etherifying or esterifying the hydroxy group toform a conventional hydrolyzable ether or ester group can be utilized incarrying out this reaction. The preferred protecting group formed by R₆' is tetrahydropyranyloxy. On the other hand, where R₆ ' is --OR₈ ' thiscompound is formed by etherification with a lower alkyl halide. Any ofthe conditions conventional in forming a lower alkyl ether can beutilized in this conversion.

The compound of formula IV is converted to the compound of formula V bytreating the compound of formula IV with a reducing agent. In carryingout this reaction, any conventional reducing agent which willselectively reduce a keto-group to a hydroxy-group can be utilized.Preferred reducing agents are the hydrides, particularly the aluminumhydrides such as alkali metal aluminum hydride, and the borohydridessuch as alkali metal borohydrides, with diisobutyl aluminum hydridebeing particularly preferred. Also, this reaction can be carried oututilizing di-(branched chain lower alkyl)boranes such asbis(3-methyl-2-butyl)borane. In carrying out this reaction, temperatureand pressure are not critical and the reaction can be carried out atroom temperature and atmospheric pressure or at elevated or reducedtemperatures and pressures. Generally, it is preferred to carry out thisreaction at a temperature of from -10° C. to the reflux temperature ofthe reaction mixture. This reduction reaction can be carried out in thepresence of an inert organic solvent. Any conventional inert organicsolvents can be utilized in carrying out this reaction. Among thepreferred solvents are dimethoxy ethylene glycol, and the ethers such astetrahydrofuran, diethyl ether and dioxane.

The compound of formula VI is obtained from the compound of formula V byreacting the compound of formula V with phosphonium salts of theformula: ##STR15## wherein R₁₀, R₁₀ ', R₁₀ " is aryl or di(loweralkyl)amino; and Y is halogen.

In accordance with this invention, it is found that the compound offormula V will react with the compound of formula X to produce acompound of the formula VI with a predominately cis double bond at the 5position of the acid chain in a solvent medium containinghexamethylphosphoramide utilizing sodium bis-trimethylsilylamide as abase. If solvents other than hexamethylphosphoramide or bases other thansodium bis-trimethylsilylamide are utilized, the compound of formula VIwill form, if at all, in poor yields. However, conventional inertorganic solvents may be mixed with the hexamethylphosphormiade to formthe solvent medium in accordance with this invention. If other solventsare utilized, these solvents can be conventional inert organic solvents.On the other hand, the solvent system can contain only thehexamethylphosphoramide. Therefore, this reaction is carried oututilizing hexamethylphosphormiade as the solvent and sodiumbis-trimethylsilyl-amide as the base. In carrying out this reaction,temperature and pressure are not critical and this reaction can becarried out at room temperature and pressure. However, if desired,higher or lower temperatures can be utilized. Generally, it is preferredto carry out this reaction at a temperature of from 0° to 50° C.

The process whereby a cis double bond is formed at the 5-position of theheptenoic acid chain can be applied to a process for preparing naturalprostaglandins. In this process, a compound of the formula: ##STR16##wherein R₆ is as above; reacted with a compound of formula X to form acompound of the formula: ##STR17## wherein R₆ is as above; and where thedouble bond at the 5-position of the heptenoic acid moiety has apredominately cis configuration. This reaction is carried out in thesolvent medium containing hexamethylphosphoramide and in the presence ofsodium bis-trimethylsilylamide as the base. The reaction is carried oututilizing the same conditions described in connection with the reactionof a compound of formula V with a compound of formula X to form acompound of formula VI.

The compound of formula VI is converted to the compound of formula I-Dby aqueous hydrolysis where the hydroxy group is protected via an etherlinkage. Any conventional method of ether hydrolysis can be utilized.Among the preferred methods of ether hydrolysis is by treating thecompound of formula VI with an aqueous acid. On the other hand, where R₆' forms --CH₂ OR₈ ', this ether linkage is not a conventionalhydrolyzable ether group and conventional ether hydrolysis will notremove the lower alkyl group. On the other hand, where R₆ forms an esterlinkage, the hydroxy group can be regenerated by treatment with a basein an aqueous medium. Any conventional method of ester hydrolysis can beutilized in this conversion.

On the other hand, the compound of formula VI above can be converted toa compound of the formula: ##STR18## wherein R₈, R₉ and R₉ ' are asabove; via an intermediate of the formula: ##STR19## wherein R₆, R₆ ',R₉ and R₉ ' are as above.

The compound of formula VI is converted to a compound of formula VIII bytreating the compound of formula VI with an oxidizing agent. Anyconventional oxidizing agent which will convert a hydroxy group to anoxo group can be utilized in carrying out this reaction. Among thepreferred oxidizing agents are chromate oxidizing agents such aschromium trioxide. Any of the conditions conventional in utilizing theseoxidizing agents can be utilized to carry out this reaction. Thecompound of formula VIII is converted to the compound of formula VII byhydrolysis in the same manner as described in connection with thehydrolysis of a compound of formula VI.

Where R₁ in the compound of formula I-C is hydrogen or lower alkyl and Ris hydrogen and the double bond is unhydrogenated, this compound has thefollowing formula: ##STR20## wherein R₄ ' is lower alkyl or hydrogen,and R₉ and R₉ ' are as above.

This compound can be prepared from a compound of formula II where R₄ ishydrogen or lower alkyl via the following intermediates: ##STR21##wherein R₄ ', R₆, R₉ and R₉ ' are as above; ##STR22##

The compound of formula II where R₄ is hydrogen or lower alkyl isconverted to the compound of formula V-A in the same manner as describedin hereinbefore for the conversion of a compound of formula IV to acompound of formula V. The compound of formula V-A is converted to thecompound of formula VI-A by reaction with the compound of formula X inthe manner described hereinbefore with regard to the conversion of acompound of formula V to a compound of formula VI. The compound offormula VI-A can be converted to a compound of the formula I-E byhydrolysis of the protecting group R₆ in the manner described inconnection with the conversion of a compound of the formula VI to acompound of the formula I-D.

On the other hand, the compound of formula VI-A can be oxidized to acompound of the formula: ##STR23## wherein R₄ ', R₆, R₉ and R₉ ' are asabove in the same manner as described in connection with the oxidationof a compound of formula VI to a compound of formula VIII. The compoundof formula VIII-A can be converted to the compound of the formula:##STR24## wherein R₄ ', R₉ and R₉ ' are as above; by hydrolysis in themanner described in connection with the conversion of the compound offormula VI to a compound of the formula I-D.

The compounds of formula VI, VI-A, VIII and VIII-A can be converted to acompound of the formula: ##STR25## wherein R₂, R₃, R₉ and R₉ ' are asabove; and R₇ is --CH₂ OR₈ or lower alkyl or hydrogen, by hydrogenation.Any conventional method of hydrogenation such as catalytic hydrogenationcan be utilized to carry out this conversion. Among the preferredmethods of hydrogenation is by reacting the compounds of formula VI,VI-A, VIII and VIII-A with hydrogen in the presence of a noble metalcatalyst such as platinum or palladium under conditions conventional forsuch hydrogenation. After hydrogenation, the protecting group can beremoved by hydrolysis.

The compounds of formulae I-D, I-E, VII, VII-A and IX can be convertedto a compound of the formula: ##STR26## wherein R₂, R₃, R₇, R₉ and R₉ 'are as above; R' is lower alkyl; and the dotted bond can be optionallyhydrogenated; by esterification with diazomethane or a reactivederivative of a lower alkanol such as a lower alkyl halide. Anyconventional conditions utilizing in this esterifying method can beutilized in forming the compound of formula XI from the compounds offormulae I-D, I-E, VII, VII-A or IX. On the other hand, the compound offormula XI can be formed from the compounds of the formulae VI, VI-A,VIII or VIII-A where R₆ and R₆ ' are hydroxy protected with ahydrolozable ether group by esterification as described above to form acompound of the formula: ##STR27## wherein R', R₂, R₃, R₉ and R₉ ' areas above; R₄ " is hydrogen, lower alkyl, or --CH₂ R₆ "; and R₆ " ishydroxy protected with a hydrolozable ether group and the dotted bondcan be optimally hydrogenated. The compound of formula XI-A is convertedto the compound of formula XI by conventional ether hydrolysis, asdescribed above.

The compound of formula II wherein R₁ ' is lower alkyl, can be convertedto the compound of formula I wherein R₁ is: ##STR28## via the followingintermediates: ##STR29## wherein R₁ ', R₆, R₉ and R₉ ' are as above;##STR30## wherein R₆, R₉ and R₉ ' are as above.

The compound of formula II wherein R₄ is --COOR₁ ', R₁ ' is lower alkyl,R₉ and R₉ ' are hydrogen and their methods of preparation are disclosedin Ser. No. 300,633, filed Oct. 25, 1972, Rosen et al. (note compoundXXI-C and Example 20 in Ser. No. 300,633, filed Oct. 25, 1972). Thecompound of formula II where R₄ is --COOR₁ and R₁ ' is lower alkyl isconverted to the compound of formula XII in the same manner as describedabove in connection with the conversion of a compound of formula IV toformula V.

The compound of formula XII is converted to the compound of formula XIIIby reacting the compound of formula XII with the compound of formula Xin the presence of dimethylsulfoxide and an alkali metal hydride base.The dimethylsulfoxide can be utilized as a solvent as well as a reactantin this reaction. On the other hand, any conventional inert organicsolvent can be utilized in admixture with dimethylsulfoxide as theorganic solvent medium. In carrying out this reaction, alkali methalhydride is utilized as the base. On the other hand, the alkali metalhydride can be combined with dimethylsulfoxide in the form of an alkalimetal methyl sulfinylmethylide in this reaction. In carrying out thisreaction, temperature and pressure are not critical and this reactioncan be carried out at room temperature and atmospheric pressure. On theother hand, higher or lower temperatures can be utilized. Generally, itis preferred to carry out this reaction at a temperature of from -10° C.to +50° C.

The compound of formula XIII is converted to a compound of the formula:##STR31## wherein R₉ and R₉ ' are as above; by hydrolysis in the samemanner as described in connection with the hydrolysis of a compound ofthe formula VI.

The compound of formula XIII can be converted to a compound of theformula: ##STR32## wherein R₉ and R₉ ' are as above; by hydrogenation inthe same manner as described in the conversion of compounds of theformulae VI or VIII to a compound of the formula IX above.

The compound of formulae XIV and XV can be converted by esterificationwith a lower alkanol in the manner described in connection with theesterification of a compound of formulae I-D, VII and IX to form acompound of the formula: ##STR33## wherein R₁ ', R₉ and R₉ ' are asabove; and the dotted bond can be optionally hydrogenated.

The compound of formula XIII can be converted to a compound of theformula: ##STR34## wherein R₆, R₉ and R₉ ' are as above; by oxidation inthe manner described in connection with the oxidation of a compound ofthe formula VI to a compound of the formula VII. The compound of formulaXV can be hydrolyzed in the manner of the compound of formula VIII and,if desired, hydrogenated, and/or esterified in the manner describedabove to produce a compound of the formula: ##STR35## wherein R₉, R₉ 'and R are as above; and the dotted line can be hydrogenated.

Where R₁ in the compound of formula I is carboxy or loweralkoxycarbonyl, this compound can be prepared from a compound of formulaXII via the following intermediate: ##STR36## wherein R₅ isalkoxycarbonyl or carboxy; and R₉, R₉ ' and R₆ are as above. Thecompound of formula XVII is prepared from the compound of formula XII byreacting the compound of formula XII with a compound of formula X in thesame manner as described in connection with the reaction of a compoundof the formula V with a compound of formula X.

Where R₆ is an esterified hydroxy group in the compound of formula XVII,basic hydrolysis will produce a compound of the formula: ##STR37##wherein R₉ and R₉ ' are as above. Any conventional means of basichydrolysis to cleave an ester group can be utilized in carrying out thisconversion. On the other hand, R₆ in the compound of formula XVII is anetherified hydroxy group, this compound is converted to the compound ofthe formula: ##STR38## wherein R₉, R₉ ' and R₅ are as above; by acidhydrolysis. Any conventional method of acid hydrolysis generally used inhydrolyzing ether groups can be utilized in this conversion. Thecompound of formula XX can, if desired, be converted to a compound offormula XIX by basic hydrolysis in the manner described above.

If desired, the compound of formula XX can be esterified with a loweralkanol or a lower alkyl halide by conventional esterificationtechniques in the manner described above to produce a compound of theformula: ##STR39## wherein R₉, R₉ ', R₅ and R' are as above.

The compound of formula XIX, XX and XXI can be converted to a compoundof the formula: ##STR40## wherein R₅, R₉, R₉ ' and R are as above; byhydrogenation in the manner described above in connection with theconversion of a compound of formulae VI and VIII to a compound of theformula IX.

The compound of formula XVII can be oxidized in the manner described inconnection with the oxidation of a compound of formula VI to form acompound of the formula: ##STR41## wherein R₅, R₉, R₉ ' and R₆ are asabove.

The compound of formula XXIV can be hydrolyzed in the manner of thecompound of formula XVII and, if desired, esterified and/or hydrogenatedin the manner described hereinbefore to form a compound of the formula:##STR42## wherein R₅, R₉, R₉ ' and R are as above; and the dotted bondcan be optionally hydrogenated.

Where R₆ is an ether group, the preferred ether groups are2-tetrahydropyranyloxy and dimethyl-tert-butylsilyloxy. These etherstarting materials of formula II are prepared from compounds of theformula: ##STR43## wherein R₉ and R₉ ' are as above. The compounds offormula II-B where R₉ and R₉ ' are hydrogen and their method ofpreparation are disclosed in U.S. patent application Ser. No. 300,633,filed Oct. 25, 1972, Rosen et al. (Please note compound XXI-C andExample 14 of U.S. patent application Ser. No. 300,633). The compoundsof formula II-B are etherified in the conventional manner by reactingwith an alcohol or a reactive derivative thereof under conditionsconventional in the art.

The compound of formula II can be obtained by first reacting a compoundof the formula: ##STR44## wherein R₄ is as above; with either aphosphorane of the formula: ##STR45## wherein R₁₀, R₁₀ ', R₁₀ ", R₉, R₉' and Y are as above; or a phosphonate of the formula: ##STR46## whereinR₉ and R₉ ' are as above; and R₁₅ and R₁₅ ' are aryl, aryloxy or loweralkoxy; to form a compound of the formula: ##STR47## wherein R₄, R₉ andR₉ ' are as above; followed by reducing the compound of formula XXXV toform a compound of the formula: ##STR48## wherein R₄, R₉ and R₉ ' are asabove; and finally etherifying or esterifying the free hydroxy group.

The reaction of the compound of formula XXVII with the phosphonium saltof formula XXIX to produce a compound of formula XXV is carried out viaa Wittig reaction. Any of the conditions conventional in Wittigreactions can be utilized in carrying out this reaction.

The reaction of the compound of formula XXVIII with the phosphonate offormula XXX to produce a compound of formula XXXVI is carried out via aHorner reaction. Any of the conditions conventional in Horner typereactions can be utilized in carrying out this reaction.

The compound of formula XXVIII where R₄ is --COOR₁ ' and its method ofpreparation is disclosed in U.S. Patent Application Ser. No. 300,633,filed Oct. 25, 1972, Rosen et al. (Please note the compound of formulaIII and Example 12 of Ser. No. 300,633). The compound fo formula XXVIIIwhere R₄ is lower alkyl or hydrogen and its method of preparation isdisclosed in U.S. Patent Application Ser. No. 381,322, filed July 20,1973. (Please note, the compound of formula XVI and Examples 43 and 44of Ser. No. 381,322). The disclosure of both U.S. Patent ApplicationSer. No. 300,633 and Ser. No. 381,322 are incorporated by reference.

The compound of formula XXX, where R₉ is fluoro, and R₉ ' is hydrogen orlower alkyl, is prepared by reacting a lithium salt of the formula:##STR49## wherein R₁₅ is as above; with a compound of the formula:##STR50## wherein R₂₅ is lower alkyl, and R₉ ' is as above. Any of theconditions conventional for reacting a lithium salt with an ester toform an addition product can be used in this reaction.

The compound of formula XXX where R₉ is alkyl and R₉ ' is hydrogen oralkyl can be prepared by reacting the compound of formula XXXI with acompound of the formula: ##STR51## wherein R₂₅ is as above and X is ahalogen. Any of the conditions conventional in forming addition productsby reacting a lithium salt with an acid chloride can be used in carryingout this reaction.

The compound of formula XXIX where R₉ and R₉ ' are not both hydrogen areprepared by reacting a compound of the formula: ##STR52## wherein R₁₉ ishydrogen, lower alkyl or fluoro; and R₁₉ ' is lower alkyl or hydrogenwith the proviso that at least one of R₁₉ and R₁₉ ' is other thanhydrogen; and X is as above; with a compound of the formula: ##STR53##wherein R₁₀, R₁₀ ' and R₁₀ " are as above utilizing conventional Wittigconditions.

The compound of formula XXXVI can be obtained by treating the compoundof formula XXXV with a reducing agent. In carrying out this reaction,any conventional reducing agent which will selectively reduce aketo-group to a hydroxy group can be utilized. Preferred reducing agentsare the hydrides, particularly the aluminum hydrides, such as the alkalimetal aluminum hydrides, and the borohydrides, such as the alkali metalborohydrides, with zinc borohydride being quite particularly preferred.In carrying out this reaction, temperature and pressure are notcritical, and the reaction can be carried out at room temperature andatmospheric pressure or at elevated or reduced temperatures andpressures. Generally, it is preferred to carry out this reaction at atemperature of from -10° C. to the reflux temperature of the reactionmixture. This reduction reaction can be carried out in the presence ofan inert organic solvent. Any conventional inert organic solvent orwater can be utilized in carrying out this reaction, such as theconventional, inert organic solvents hereinbefore mentioned. Among thepreferred solvents are dimethoxy ethylene glycol and the ethers, such astetrahydrofuran, diethyl ether and dioxane.

The compound of formula XXXVI may be separated into its two isomers byconventional means to produce one isomer of the formula: ##STR54## andthe other isomer of the formula: wherein R₄ is as above. Anyconventional means of separation such as column chromatography, vaporphase chromatography, etc., can be utilized to carry out thisseparation. Either of these isomers can be utilized in accordance withthis reaction to produce the compound of formula I. The configuration ofthe hydroxy group on the octenyl side chain will be carried through theprocess of this invention so that the hydroxy group on the octenyl sidechain in the compound of formula I will have the same configuration asit has in the starting material of formula XXXVI-A or XXXVI-B.

The compound of formulae XXXVI, XXXVI-A and XXXVI-B can be converted toa compound of the formula II by esterifying or etherifying the freehydroxy group with a hydrolyzable ether or ester protecting group. Thisesterification or etherification can be carried out by conventionalesterification or etherification procedures. Among the preferredhydrolyzable ester groups are lower alkanoyloxy with acetoxy beingespecially preferred. Among the preferred hydrolyzable ether groups areincluded tetrahydropyranyl.

The following examples are illustrative but not limitative of theinvention. All temperatures are in degrees centigrade. The etherutilized in these examples was diethyl ether.

EXAMPLE 13,3abeta,4,5,6,6abeta-hexahydro-4beta[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-carbomethoxy-2-oxo-2H-cyclopenta[b]furan

1.90 g. of3,3abeta,4,5,6,6abeta-hexahydro-4beta-(3alpha-hydroxy-1-trans-octenyl)-2-oxo-2H-cyclopenta[b]furan-5alpha-carboxylicacid methyl ester was mixed with 50 ml. of methylene chloride containing1.0 ml. of freshly distilled dihydropyran and a trace ofp-toluenesulfonic acid. After 30 minutes, the solvent was evaporated andthe residual oil purified by column chromatography over silica gel toyield 2.43 g. (100%)3,3abeta,4,5,6,6abeta-hexahydro-4beta[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-carbomethoxy-2-oxo-2H-cyclopenta[b]furan.

EXAMPLE 23,3abeta,4,5,6,6abeta-hexahydro-4beta[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-ol

318 mg. (0.8 mmol) of3,3abeta,4,5,6,6abeta-hexahydro-4beta[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-carbomethoxy-2-oxo-2H-cyclopenta[b]furanwas reacted with a 100% excess of bis-3-methyl-2-butylborane in 25 ml.of tetrahydrofuran at 0° C. under argon for 20 hours. After this period,5 ml of 3 N aqueous sodium acetate and 1 ml. of 30% by weight aqueoushydrogen peroxide were added and the reaction was allowed to warm toroom temperature. After 1 hour, the mixture was cooled to 0° C. and theorganic layer separated by addition of anhydrous potassium carbonate.Evaporation of the dried (MgSO₄) organic layer gave 237 mg. (74%) ofpure3,3abeta,4,5,6,6abeta-hexahydro-4beta[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-olafter column chromatography over silica gel.

EXAMPLE 37-{3alpha-carbomethoxy-5-alpha-hydroxy-2beta[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-1alpha-cyclopentyl}-cis-5-heptenoic acid

414 mg. of3,3abeta,4,5,6,6abeta-hexahydro-4beta-[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-olwas reacted under argon in 15 ml. of hexamethylphosphoric triamide with2.8 equivalents of the Wittig reagent generated from the reaction ofsodium bis-trimethylsilyl amide with(4-carboxybutyl)triphenylphosphonium bromide. After one hour, thereaction was neutralized with acetic acid and the solvent removed at40°-50° C. at high vacuo. Column chromatography of the residual materialover silica gel yielded7-{3alpha-carbomethoxy-5alpha-hydroxy-2beta-[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-1alpha-cyclopentyl}-cis-5-heptenoicacid.

EXAMPLE 43,3abeta,4,5,6,6abeta-hexahydro-4beta(3alpha-dimethyl-tert-butylsilyloxy-1-trans-octenyl)5alpha-carbomethoxy-2-oxo-2H-cyclopenta[b]furan

683 mg. (2.13 mmol) of3,3abeta,4,5,6,6abeta-hexahydro-4beta-(3alpha-hydroxy-1-trans-octenyl)-2-oxo-2H-cyclopenta[b]furan-5alpha-carboxylicacid methyl ester was mixed with 393 mg. (2.56 mmol) ofdimethyl-tert-butylsilyl chloride, 362 mg. (5.33 mmol) of imidazole, and3 ml. of N,N-dimethylformamide. After 20 hours at 35° C. the reactionmixture was diluted with methylene chloride, washed with water and dried(MgSO₄). Evaporation of the solvent gave 1.01 g. (98%) of3,3abeta,4,5,6,6abeta-hexahydro-4beta-(3alpha-dimethyl-tert-butylsilyloxy-1-trans-octenyl)-5alpha-carbomethoxy-2-oxo-2H-cyclopenta[b]furan;m.p. 87°-89° C. from hexane.

EXAMPLE 53,3abeta,4,5,6,6abeta-hexahydro-4beta(3alpha-dimethyl-tert-butylsilyloxy-1-trans-octenyl)-5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-ol

1.4 g. (3 mmol) of3,3abeta,4,5,6,6abeta-hexahydro-4beta(3alpha-dimethyl-tert-butylsilyloxy-1-trans-octenyl)-5alpha-carbomethoxy-2-oxo-2H-cyclopenta[b]furanwas reacted with 100% excess of bis-3-methyl-2-butyl borane in 50 ml. oftetrahydrofuran under argon at 0° C. After 20 hours, the mixture wasoxidized with 6 ml. of 30% by weight aqueous hydrogen peroxide in thepresence of 30 ml. of 3 N aqueous sodium acetate. The organic layer wasseparated by the addition at 10° C. of anhydrous potassium carbonate,dried (MgSO₄) and evaporated to give 1.3 g. (93%) of3,3abeta,4,5,6,6abeta-hexahydro-4beta-(3alpha-dimethyl-tert-butylsilyloxy-1-trans-octenyl)-5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-olafter purification by column chromatography over silica gel.

EXAMPLE 67-[3alpha-carbomethoxy-5alpha-hydroxy-2beta-(3alpha-dimethyl-tert-butylsilyloxy-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoicacid

213 mg. of3,3abeta,4,5,6,6abeta-hexahydro-4beta-(3alpha-dimethyl-tert-butylsilyloxy-1-trans-octenyl)-5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-olwas reacted in 15 ml. of hexamethylphosphoric triamide at 25° C. underargon with 2.8 equivalents of the Wittig reagent generated by thereaction of sodium bis-trimethylsilyl amide with(4-carboxybutyl)-triphenylphosphonium bromide. After one hour, thereaction was poured into 50 ml. of a 1:1 parts by volume mixture ofsaturated aqueous sodium chloride solution and 30% by weight aqueousphosphoric acid. The resulting mixture was extracted with cyclohexane.Evaporation of the dried (Na₂ SO₄) extracts yielded 110 mg. of crude7-[3alpha-carbomethoxy-5alpha-hydroxy-2beta-(3alpha-dimethyl-tert-butylsilyloxy-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoicacid which was purified by column chromatography over silica gel.

EXAMPLE 77-[3alpha-carbomethoxy-5alpha-hydroxy-2-beta-(3alpha-hydroxy-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoicacid

100 mg. of7-{3alpha-carbomethoxy-5alpha-hydroxy-2beta-[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-1-alpha-cyclopentyl}-cis-5-heptenoicacid was heated at 35° C. in 3 ml. of 2:1 parts by volume aceticacid-water for 16 hours. The volatile components were evaporated at 25°C., and 0.5 mmHg, and the crude7-[3alpha-carbomethoxy-5alpha-hydroxy-2beta-(3alpha-hydroxy-1-trans-octenyl)-1-alpha-cyclopentyl]-cis-5-heptenoicacid purified by column chromatography over silica gel.

EXAMPLE 8

By the procedure of Example7,7-[3alpha-carbomethoxy-5alpha-hydroxy-2beta-(3alpha-dimethyl-tert-butylsilyloxy-1-trans-octenyl)-1-alpha-cyclopentyl]-cis-5-heptenoicacid was converted to7-[3alpha-carbomethoxy-5alpha-hydroxy-2beta-(3alpha-hydroxy-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoicacid.

EXAMPLE 9 Methyl7-[3alpha-carbomethoxy-5alpha-hydroxy-2beta-(3alpha-hydroxy-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoate

7-[3alpha-carbomethoxy-5alpha-hydroxy-2beta-(3alpha-hydroxy-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoicacid was treated with a 50% molar excess of diazomethane in diethylether. The solvent was removed with a stream of nitrogen to yield methyl7-[3alpha-carbomethoxy-5alpha-hydroxy-2beta-(3alpha-hydroxy-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoate.

EXAMPLE 107-[3alpha-carboxy-5-alpha-hydroxy-2beta-(3alpha-hydroxy-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoicacid

100 mg. of7-[3alpha-carbomethoxy-5-alpha-hydroxy-2beta-(3alpha-hydroxy-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoicacid was treated with 2.5 equivalents of lithium hydroxide in 5 ml. of10:1 parts by volume methanol-water at 25° C. for 6 hours. The mixturewas treated with excess Dowex 50W-X8 acid ion exchange resin, filtered,and the solvent evaporated to yield7-[3alpha-carboxy-5alpha-hydroxy-2beta-(3alpha-hydroxy-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoicacid; m.p. 105°-107° C. after purification by column chromatography oversilica gel.

EXAMPLE 117-[3alpha-(methylsulfinylacetyl)-5alpha-hydroxy-2beta-(3alpha-hydroxy-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoicacid

400 mg. of3,3abeta,4,5,6,6abeta-hexahydro-4beta-[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-olwas reacted in 15 ml. of dimethylsulfoxide at 25° C. with 2.8equivalents of the Wittig reagent generated by the reaction of sodiummethylsulfinylmethylide with (4-carboxybutyl)-triphenylphosphoniumbromide. After 5 hours, the solvent was evaporated at 25° C. (0.1 mmHg.)and the residual paste mixed with 3 ml. of water and 6 ml. acetic acid.This mixture was maintained at 35° C. for 16 hours then the volatilecomponents were removed at 25° C. (0.1 mmHg.).7-[3alpha-(methylsulfinylacetyl)-5alpha-hydroxy-2beta-(3alpha-hydroxy-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoicacid was isolated from the residual material by column chromatographyover silica gel.

EXAMPLE 12 Methyl7-[3alpha-(methylsulfinylacetyl)-5alpha-hydroxy-2beta-(3alpha-hydroxy-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoate

100 mg. of7-[3alpha-(methylsulfinylacetyl)-5alpha-hydroxy-2beta-(3alpha-hydroxy-1-trans-octenyl)-1-alpha-cyclopentyl]-cis-5-heptenoicacid was dissolved in 1:1 parts by volume methylene chloride ethyl etherand treated with a 50% molar excess of diazomethane. The solvent wasremoved with a stream of nitrogen to yield methyl7-[3alpha-methylsulfinylacetyl-5alpha-hydroxy-2beta-(3alpha-hydroxy-1-trans-octenyl)1alpha-cyclopentyl]-cis-5-heptenoate which was purified by columnchromatography over silica gel.

EXAMPLE 133,3abeta-4,5,6,6abeta-hexahydro-4beta-[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-hydroxymethyl-2H-cyclopenta[b]furan-2-one

To a solution of 0.90 g. (2.36 mmole) of3,3abeta-4,5,6,6abeta-hexahydro-4beta-[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-carboxy-2H-cyclopenta[b]furan-2-onein 10 ml. of dry tetrahydofuran kept at ice bath temperature was added20 ml. of a 0.146 molar borane solution in tetrahydrofuran. Afterstirring at this temperature for one hour and room temperature for 25minutes, the reaction mixture was decomposed with 5 ml. of water andsaturated with sodium chloride. The tetrahydrofuran layer was decantedfrom the aqueous solution, combined with the ethyl acetate extracts ofthe aqueous layer, dried (sodium sulfate), and the solvent removed undervacuum leaving 0.80 g. of residue. This material was shown to behomogeneous by tlc analysis and was used directly in the nextexperiment. Passing the product through a silica gel column yielded ananalytical sample of3,3abeta-4,5,6,6abeta-hexahydro-4beta-[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-hydroxymethyl-2H-cyclopenta[b]furan-2-one.

EXAMPLE 143,3abeta,4,5,6,6abeta-hexahydro-4beta-[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-[(2-tetrahydropyranyloxy)methyl]-2H-cyclopenta[b]furan-2-one

To a solution of 0.95 g. (2.6 mmol) of3,3abeta-4,5,6,6-abeta-hexahydro-4beta-[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-hydroxymethyl-2H-cyclopenta[b]furan-2-onein 35 ml. of dry methylene chloride was added 0.35 g. of freshlydistilled dihydropyran and 4 mg. of p-toluenesulfonic acid. The mixturewas stirred at room temperature for ten minutes and then washed with a5% by weight aqueous sodium bicarbonate solution. The methylene chloridesolution was dried (Na₂ SO₄) and the solvent and excess dihydropyranremoved under vacuum to give 1.144 g. of crude product. An analyticalsample of3,3abeta-4,5,6,6-abeta-hexahydro-4beta-[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5-alpha-[(2-tetrahydropyranyloxy)methyl]-2H-cycopenta[b]furan-2-onewas obtained by column chromatography.

EXAMPLE 153,3abeta-4,5,6,6abeta-hexahydro-4beta-[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-[(2-tetrahydropyranyloxy)methyl]-2H-cyclopenta[b]furan-2-ol

Twenty milliliters of toluene were removed by distillation from asolution of 1.144 g. of3,3abeta,4,5,6,6abeta-hexahydro-4beta-[3-alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-[(2-tetrahydropyranyloxy)methyl]-2H-cyclopenta[b]furan-2-onein 60 ml. of toluene. To this solution kept under argon and in a DryIce-acetone bath was added 3 ml. of a 2.3 molar solution of diisobutylaluminum hydride in hexane. After stirring for 20 minutes at dry icetemperature, the reaction mixture was decomposed with 3 ml. of methanoland let warm up to room temperature. After the addition of 1 ml. ofwater and 3 g. of Celite, the reaction mixture was stirred for another30 minutes, filtered and dried (Na₂ SO₄). The solvent was removed undervacuum to give 1.129 g. of crude product. Chromatography on silica gelof the crude material yielded 0.928 g. of3,3abeta-4,5,6,6abeta-hexahydro-4beta-[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-[(2-tetrahydropyranyloxy)methyl]-2H-cyclopenta[b]furan-2-ol.

EXAMPLE 16 11-homo-prostaglandin F₂ α,11a,15-bis-(tetrahydropyranylether)-preparation in dimethyl sulfoxide

To 4 ml. of a 0.6 molar solution of sodium methylsulfinyl carbabion indimethylsulfoxide was added 0.53 g. (1.2 mmole) of(4-carboxybutyl)triphenylphosphonium bromide in 2 ml. of drydimethylsulfoxide. To this Wittig reagent was added 0.25 g. (0.5 mmole)of3,3abeta-4,5,6,6abeta-hexahydro-4beta[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-[(2-tetrahydropyranyloxy)methyl]-2H-cyclopenta[b]furan-2-olin 10 ml. of dimethylsulfoxide. The reaction mixture was stirred for 30hours at room temperature, then chilled in an ice bath, and decomposedwith 10 ml. of 0.2 N sulfuric acid and followed by 2 ml. of 5% by weightof sodium bicarbonate solution. The solvent was removed in vaccum andresidue dissolved in 10 ml. of water. The reaction mixture was adjustedto pH 4 at ice temperature with dilute sulfuric acid and extracted withethyl acetate three times. The combined extracts were washed with asaturated sodium chloride solution, dried (Na₂ SO₄), and solventremoved. The residue was chromatographed on silica gel to yield a majorproduct,2alpha-(3-methylsulfinyl-2-hydroxypropyl)-4alpha-[(2-tetrahydropyranyloxy)methyl]-3beta[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-1-alpha-cyclopentanoland a minor product, 11-homo-prostaglandin F₂α,11a,15-bis(tetrahydropyranyl ether).

EXAMPLE 17 11-Homo-prostaglandin F₂ α,11a,15-bis-(tetrahydropyranylether)-preparation in hexamethylphosphoramide

To a solution of 666 mg. (1.48 mmole) of(4-carboxybutyl)-triphenylphosphonium bromide in 20 ml. ofhexamethylphosphoramide was added 550 mg. (2.96 mmole) of sodiumbis-trimethylsilyl amide in 30 ml. of hexmethylphosphoramide. To theabove solution was then added 240 mg. (0.53 mmole) of3,3abeta-4,5,6,6-abeta-hexahydro-4beta-[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-[(2-tetrahydropyranyloxy)methyl]-2H-cyclopenta[b]furan-2-olin 10 ml. of hexamethylphosphoramide. After stirring at room temperaturefor 2 hours the reaction mixture was poured into 100 g. of ice-water,acidified to pH 3.5 with dilute sulfuric acid and extracted withcyclohexane (4 times). The cyclohexane extracts were washed withsaturated aqueous sodium chloride solution, dried (Na₂ SO₄), and solventremoved to yield 300 mg. of an oil which was chromatographed on silicagel to yield 11-homo-prostaglandin F₂ α,11a,15-bis-(tetrahydropyranylether).

EXAMPLE 18 11-Homo-prostaglandin F₂α

A solution of 200 mg. of 11-homo-prostaglandin F₂α,11a-15-bis-(tetrahydropyranyl ether) in 5 ml. of a 3:1 parts by volumeacetic acid/water solution was kept at 35° C. for 15 hours. The solventwas then removed under high vacuum and the residue purified via columnchromatography to give 11-homo-prostaglandin F₂α.

EXAMPLE 19 11-Homo-prostaglandin E₂,11a,15-bis-(tetrahydropyranyl ether)

To a mixture of 3 g. of chromium trioxide and 4.7 g. of pyridine in 75ml. of methylene chloride was added at 0° C. 2.2 g. of11-homo-prostaglandin F₂ α,11a,15-bis (tetrahydropyranyl ether) in 25ml. of methylene chloride. The mixture was stirred for one hour at roomtemperature and then filtered through Celite. The Celite was washed withmethylene chloride and the combined methylene chloride solution washedwith dilute aqueous hydrochloric acid to remove any remaining pyridine.The solvent was then removed under vacuum and the residue purified viacolumn chromatography to give 11-homo-prostaglandinE₂,11a,15-bis-(tetrahydropyranyl ether).

EXAMPLE 20 11-Homo-prostaglandin-F₁α

To a cooled (-20° C.) solution of 0.50 g. of 11-homo-prostaglandin F₂α,11a,15-bis (tetrahydropyranyl ether) in 20 ml. of methane was added 150mg. of a 5% by weight palladium on charcoal catalyst and the mixturehydrogenated under 1 atm. of hydrogen. After 1 mol. of hydrogen wastaken up, the mixture was passed through a bed of Celite. After removalof solvent the residue was treated with 3:1 parts by weight aceticacid/water solution for 15 hours at 35° C. The solvent was taken offunder high vacuum and the residue purified via column chromatography togive 11-homo-prostaglandin F₁α.

EXAMPLE 21 Dimethyl(2-oxo-3-fluoro-heptyl)phosphonate

To a solution of 7.7 g. (0.06 mole) of dimethyl methyl-phosphonate in 80ml. of tetrahydrofuran at -73° C. was added dropwise 43.4 ml. of a 1.42molar solution of butyl lithium in hexane. After stirring for 5 minutes,a solution of 4 g. (0.03 mole) of ethyl 2-fluorohexanoate in 20 ml. oftetrahydrofuran was added dropwise. The resulting solution was thenallowed to warm to 0° and then acidified (pH 3) with 2 N sulfuric acid.The mixture was then extracted with hexane, the hexane solution washedwith a saturated sodium chloride solution and then dried (MgSO₄). Thesolvent was then removed under reduced pressure and the residuedistilled to give 5.8 g. of dimethyl(2-oxo-3-fluoro-heptyl)phosphonate,b.p. 116°-118°/0.4 mm.

EXAMPLE 22 Dimethyl(3,3-dimethyl-2-oxo-heptyl)phosphonate

A solution of 46.4 g. of dimethyl methyl-phosphonate in 900 ml. oftetrahydrofuran was cooled under argon to -78° (dry ice-acetone bath)and treated dropwise with 220 ml. of 1.54 M n-butylithium in hexane.After 5 minutes, 27.5 g. of 2,2-dimethylhexanoyl chloride (b.p.68°-70°/19 mm; prepared from 2,2-dimethylhexanoic acid and excess oxalylchloride) was added dropwise. The mixture was stirred at -78° for 3hours, then allowed to warm to 0° over a 30 minute period. The mixturewas poured into a separatory funnel containing 50 ml. of water and 2.5l. of diethyl ether. The layers were separated and the organic layerwashed with 4×100 ml. saturated sodium chloride solution, dried (MgSO₄)and the ether evaporated at 40°. The residual oil was distilled atreduced pressure to give 37.1 g. of dimethyl(3,3-dimethyl-2-oxo-heptyl)phosphonate; b.p. 97°-103°/0.06 mmHg.

EXAMPLE 233,3abeta,4,5,6,6abeta-hexahydro-4beta(4,4-dimethyl-3-oxo-1-trans-octenyl)-5alphacarbomethoxy-2H-cyclopenta[b]furan-2one

To a mixture of 3.5 g. of sodium hydride/mineral oil (55% by weightsodium hydride) in 500 ml. of dry dimethoxyethane under argon was addeda solution of 20.0 g. of dimethyl(3,3-dimethyl-2-oxo-heptyl)phosphonatein 100 ml. of dimethoxyethane. The mixture was vigorously stirred for 2hours at room temperature. A solution of 16.0 g. of3,3abeta-4,5,6,6abeta-hexahydro-4beta-formyl-5alphacarbomethoxy-2-oxo-2H-cyclopenta[b]furan in 120 ml. of dimethoxyethanewas added and the mixture stirred for 3 hours at room temperature. Afterthis time, 300 ml. of water was added and the mixture poured into aseparatory funnel containing 2 l. of ethyl ether. The layers wereseparated, and the ether layer was washed with saturated sodium chloridesolution, dried (Na₂ SO₄) and the ether evaporated at 40°. The residualoil solidified upon cooling and was recrystallized from diethylether/hexane (7:3) to give 23.0 g. of3,3abeta,4,5,6,6abeta-hexahydro-4beta(4,4-dimethyl-3-oxo-1-trans-octenyl)-5alpha carbomethoxy-2H-cyclopenta[b]furan, m.p.71°-72°.

EXAMPLE 24 3,3abeta,4,5,6,6abeta-hexahydro-4beta(4,4-dimethyl-3alphahydroxy-1-trans-octenyl)5alpha carbomethoxy-2H-cyclopenta[b]furan-2-oneand3,3abeta,4,5,6,6-abeta-hexahydro-4beta(4,4-dimethyl-3beta-hydroxy-1-trans-octenyl)-5alphacarbomethoxy-2H-cyclopenta[b]furan-2-one

To a solution of 4.4 g. (13.1 mmol) of3,3abeta,4,5,6,6abeta-hexahydro-4beta(4,4-dimethyl-3-oxo-1-trans-octenyl)-5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-onein 100 ml. of 1,2-dimethoxyethane was added a solution of 15 mmol ofzinc borohydride in 150 ml. of 1,2-dimethoxyethane. The mixture wasstirred for 5 hours then poured into a mixture of 5 ml. of 4 N aqueoussulfuric acid, 100 g. of ice, and 300 ml. of diethyl ether. The layerswere separated and the water layer extracted with 2×200 ml. of ether.The combined ether extracts were washed with 3×30 ml. of saturatedaqueous sodium chloride solution, dried (Na₂ SO₄) and the solventevaporated to give colorless oil which upon column chromatography, oversilica gel yielded pure3,3abeta,4,5,6,6abeta-hexahydro-4beta(4,4-dimethyl-3alpha-hydroxy-1-trans-octenyl)-5alphacarbomethoxy-2H-cyclopenta[b]furan-2-one (m.p. 61°-62°) and3,3abeta,4,5,6,6abeta-hexahydro-4beta(4,4-dimethyl-3beta-hydroxy-1-trans-octenyl)-5alphacarbomethoxy-2H-cyclopenta[b]furan-2-one in approximately equal amounts.

EXAMPLE 253,3abeta,4,5,6,6abeta-hexahydro-4beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]5alphacarbomethoxy-2H-cyclopenta[b]furan-2-one

By the procedure of Example 1,3,3abeta,4,5,6,6abeta-hexahydro-4beta(4,4-dimethyl-3alpha-hydroxy-1-trans-octenyl)-5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-onewas converted to3,3abeta,4,5,6,6abeta-hexahydro-4beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1trans-octenyl]-5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-one.

EXAMPLE 263,3abeta,4,5,6,6abeta-hexahydro-4beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-5-alphacarbomethoxy-2H-cyclopenta[b]furan-2-ol

By the procedure of Example 2,3,3abeta,4,5,6,6abeta-hexahydro-4beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alphacarbomethoxy-2H-cyclopenta[b]furan-2-one was converted to3,3abeta,4,5,6,6abeta-hexahydro-4beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1-transoctenyl]-5alphacarbomethoxy-2H-cyclopenta[b]furan-2-ol.

EXAMPLE 277-{3alpha-carbomethoxy-5alpha-hydroxy-2beta[4,4-dimethyl-3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-1alpha-cyclopentyl}-cis-5-heptenoic acid

By the procedure of Example 3,3,3abeta,4,5,6,6abeta-hexahydro-4beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alphacarbomethoxy-2-H-cyclopenta[b]furan-2-ol was converted to 7-{3-alpha-carbomethoxy-5alpha-hydroxy-2beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-1-alpha-cyclopentyl}-cis-5-heptenoicacid.

EXAMPLE 287-[3alpha-carbomethoxy-5alpha-hydroxy-2beta-(4,4-dimethyl-3alpha-hydroxy-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoicacid

By the procedure of Example 7,7-{3alpha-carbomethoxy-5alpha-hydroxy-2beta[4,4-dimethyl-3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-1alpha-cyclopentyl}-cis-5-heptenoicacid was converted to7-[3alpha-carbomethoxy-5-alpha-hydroxy-2beta-(4,4-dimethyl-3alpha-hydroxy-1-trans-octenyl)-1-alpha-cyclopentyl]-cis-5-heptenoicacid.

EXAMPLE 297-{3alpha-carbomethoxy-5-oxo-2beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-1alpha-cyclopentyl]-cis-5-heptenoic acid

By the procedure of Example 19,7-{3alpha-carbomethoxy-5alpha-hydroxy-2beta[4,4-dimethyl-3alpha-(2-tetrahydropyranyloxy)-1-transoctenyl]-1alpha-cyclopentyl}-cis-5-heptenoic acid was converted to7-{3alpha-carbomethoxy-5-oxo-2beta[4,4-dimethyl-3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-1alpha-cyclopentyl}-cis-5-heptenoic acid.

EXAMPLE 307-[3alpha-carbomethoxy-5-oxo-2beta(4,4-dimethyl-3alpha-hydroxy-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoic acid

By the procedure of Example 7,7-{3alpha-carbomethoxy-5-oxo-2beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-1alpha-cyclopentyl}-cis-5-heptenoic acid was converted to7-[3-alpha-carbomethoxy-5-oxo-2beta(4,4-dimethyl-3alpha-hydroxy-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoic acid.

EXAMPLE 313,3abeta,4,5,6,6abeta-hexahydro-4beta(4-fluoro-3-oxo-1-trans-octenyl)-5alphacarbomethoxy-2H-cyclopenta[b]furan-2-one

By the procedure of Example 23,3,3abeta,4,5,6,6abeta-hexahydro-4-beta-formyl-5alpha-carbomethoxy-2-oxo-2H-cyclopenta[b]furanwas reacted for 10 hours with dimethyl(2-oxo-3-fluoro-heptyl)phosphonate to produce3,3abeta,4,5,6,6abeta-hexahydro-4-beta(4-fluoro-3-oxo-1-trans-octenyl)-5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-one.

EXAMPLE 323,3abeta,4,5,6,6abeta-hexahydro-4beta(4-fluoro-3alpha-hydroxy-1-trans-octenyl)-5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-oneand3,3abeta,4,5,6,6abeta-hexahydro-4beta(4-fluoro-3beta-hydroxy-1-trans-octenyl)-5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-one

By the procedure of Example 24,3,3abeta,4,5,6,6abeta-hexahydro-4beta(4-fluoro-3-oxo-1-trans-octenyl)-5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-one was reacted with zinc borohydride to form a mixture of3,3abeta,4,5,6,6abeta-hexahydro-4beta(4-fluoro-3alpha-hydroxy-1-trans-octenyl)-5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-oneand 3,3abeta,4,5,6,6abeta-hexahydro-4beta(4-fluoro-3beta-hydroxy-1-trans-octenyl)-5-alpha-cabomethoxy-2H-cyclopenta[b]furan-2-onewhich was separated by column chromatography over silica gel.

EXAMPLE 333,3abeta,4,5,6,abeta-hexahydro-4beta[4-fluoro-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-one

By the procedure of Example 1, 3,3abeta,4,5,6,6abeta-hexahydro-4beta(4-fluoro-3alpha-hydroxy-1-trans-octenyl)-5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-onewas converted to3,3abeta,4,5,6,6abeta-hexahydro-4beta[4-fluoro-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-one.

EXAMPLE 343,3abeta,4,5,6,6abeta-hexahydro-4beta[4-fluoro-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]5-alpha-carbomethoxy-2H-cyclopenta[b]furan-2-ol

By the procedure of Example 2, 3,3abeta,4,5,6,6-abeta-hexahydro-4beta[4-fluoro-3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-onewas converted to3,3abeta,4,5,6,6abeta-hexahydro-4beta[4-fluoro-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-5-alpha-carbomethoxy-2H-cyclopenta[b]furan-2-ol.

EXAMPLE 357-{3alpha-carbomethoxy-5alpha-hydroxy-2beta-[4-fluoro-3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-1alpha-cyclopentyl}-cis-5-heptenoic acid

By the procedure of Example 3,3,3abeta,4,5,6,6abeta-hexahydro-4beta[4-fluoro-3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-olwas converted to7-{3alpha-carbomethoxy-5alpha-hydroxy-2beta-[4-fluoro-3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-1alpha-cyclopentyl}-cis-5-heptenoic acid.

EXAMPLE 367-[3alpha-carbomethoxy-5-alpha-hydroxy-2beta-(4-fluoro-3alpha-hydroxy-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoic acid

By the procedure of Example 7,7-{3alpha-carbomethoxy-5alpha-hydroxy-2beta[4-fluoro-3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-1alpha-cyclopentyl}-cis-5-heptenoic acid was converted to7-[3alpha-carbomethoxy-5alpha-hydroxy-2beta-(4-fluoro-3alpha-hydroxy-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoic acid.

EXAMPLE 377-{3-alpha-carbomethoxy-5-oxo-2beta[4-fluoro-3alpha-(2tetrahydropyranyloxy)-1-trans-octenyl]-1alpha-cyclopentyl]-cis-5-heptenoic acid

By the procedure of Example 19,7-{3alpha-carbomethoxy-5alpha-hydroxy-2beta[4-fluoro-3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-1alpha-cyclopentyl}-cis-5-heptenoic acid was converted to7-{3alpha-carbomethoxy-5-oxo-2beta[4-fluoro-3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-1alpha-cyclopentyl}-cis-5-heptenoic acid.

EXAMPLE 387-[3alpha-carbomethoxy-5-oxo-2beta(4-fluoro-3alpha-hydroxy-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoic acid

By the procedure of Example 7, 7-{3-alpha-carbomethoxy-5-oxo-2beta[4-fluoro-3-alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-1alpha-cyclopentyl]-cis-5-heptenoic acid was converted to7-[3alpha-carbomethoxy-5-oxo-2beta-(4-fluoro-3alpha-hydroxy-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoic acid.

EXAMPLE 39 11-Homo-prostaglandin E₂

By the procedure of Example 18, 200 mg of 11-homo-prostaglandin E₂, 11a,15-bis (tetrahydropyranyl ether) was converted to 11-homo-prostaglandinE₂.

EXAMPLE 40 3,3a beta 4,5,6,6a beta-Hexahydro-4-beta[4,4-dimethyl-3-alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]5-alpha carboxy-2Hcyclopenta[b]furan-2-one

To a solution of 5.95 g. (14.1 mmol) of 3,3a beta, 4,5,6,6abeta-hexahydro-4-beta[4,4-dimethyl-3-alpha(2-tetrahydropyranyloxy)1-trans-octenyl]5alpha-carbomethoxy-2H-cyclopenta[b]furan-2-one in 50 ml. of methanol wasadded 5 ml. of 7 N aqueous sodium hydroxide. The mixture was refluxedfor five hours, then condensed to a white solid under vacuo. The solidwas dissolved in 50 ml. of water, extracted with 50 ml. of ethyl ether,acidified with 4 N aqueous sulfuric acid to pH 1, and saturated withsodium chloride. An oil separated which soon solidified to yield 6.29 g.of white solid (m.p. 147°-150° C.). The solid was dissolved in 400 ml.of 3:7 (v/v) ethyl acetate/benzene and the solution brought to reflux ina Dean-Stark apparatus for 8 hours. Evaporation of the solvent in vacuoand purification by column chromatography over silica gel gave 5.46 g.(95%) of 3,3a beta, 4,5,6,6a-beta-hexahydro-4-beta[4,4-dimethyl-3-alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]5 alphacarboxy-2H-cyclopenta[b]furan-2-one; m.p. 121°-124° C.

EXAMPLE 41 3,3a beta,4,5,6,6a beta-Hexahydro-4-beta[4,4-dimethyl-3 alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]5alpha-hydroxymethyl-2H-cyclopenta [b]furan-2-one

To an ice cooled solution of 7.5 g. (18.4 mmol) of 3,3a beta, 4,5,6,6abeta-hexahydro-4-beta[4,4-dimethyl-3-alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]5 alphacarboxy-2H-cyclopenta[b]furan-2-one in 200 ml of dry tetrahydrofuranunder an argon atmosphere, was added 17.6 ml. of 1.14 Mborane-tetrahydrofuran complex (20 mmol). After one hour, 50 ml. ofmethanol was added and the mixture condensed to an oil under vacuo. Theoil was taken up in 200 ml. of ethyl ether, washed with 2×10 ml. ofsaturated aqueous sodium bicarbonate, 10 ml. of saturated aqueous sodiumchloride and dried (MgSO₄). Evaporation of the solvent in vacuo gave 8.0g. of oil which upon purification by dry column chromatography oversilica gel yielded 6.2 g (85%) of pure 3,3a beta, 4,5,6,6abeta-hexahydro-4-beta[4,4-dimethyl-3 alpha(2-tetrahydropyranyloxy)1-trans-octenyl]5-alpha hydroxymethyl-2H-cyclopenta[b]furan-2-one as a viscous oil.

EXAMPLE 42 3,3a beta,4,5,6,6a beta-Hexahydro-4-beta[4,4-dimethyl 3 alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]5alpha-[(2-tetrahydropyranyloxy)methyl]-2H-cyclopenta[b]furan-2one

By the procedure of Example 1, 3,3a beta,4,5,6,6abeta-hexahydro-4beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)1-trans-octenyl]5-alpha-hydroxymethyl-2H-cyclopenta[b]furan-2-onewas reacted with dihydropyran to give3,3beta,4,5,6,6abeta-hexahydro-4-beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]5alpha[(2-tetrahydropyranyloxy)methyl]-2H-cyclopenta[b]furan-2-oneas a viscous oil.

EXAMPLE 43 3,3a beta,4,5,6,6a beta-Hexahydro-4-beta[4,4-dimethyl-3 alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]5alpha[(2-tetrahydropyranyloxy)methyl]-2H-cyclopenta[b]furan-2-ol

By the procedure of Example 2, 6.35 g. of 3,3a beta,4,5,6,6abeta-hexahydro-4-beta[4,4-dimethyl-3-alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]5alpha[(2-tetrahydropyranyloxy)methyl]-2H-cyclopenta[b]furan-2-onewas reacted with bis (3-methyl-2-butyl)borane to yield afterpurification 5.73 g. (90%) of 3,3a beta,4,5,6,6abeta-hexahydro-4-beta[4,4-dimethyl-3-alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]5alpha[2-tetrahydropyranyloxy)methyl]-2H-cyclopenta[b]furan-2-ol as aviscous oil.

EXAMPLE 447-{3alpha-(2-tetrahydropyranyloxy)methyl-5alpha-hydroxy-2beta[4,4-dimethyl-3-alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-1alpha-cyclopentyl]cis-5-heptenoic acid

To 2.1 equivalents of the Wittig reagent generated by the reaction ofsodium bis-trimethylsilyl amide with(4-carboxybutyl)-tri-phenylphosphonium bromide in 300 ml. of hexamethylphosphoric triamide at 25° C. under argon was added ahexamethylphosphoric triamide solution of 5.67 g. of 3,3abeta,4,5,6,6abeta-hexahydro-4beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]5alpha[(2-tetrahydropyranyloxy)-methyl]-2H-cyclopenta[b]furan-2-ol.After 30 minutes the excess Wittig reagent was destroyed with glacialacetic acid and the volatile components removed by distillation at60°-75° C./0.04 mmHg. The residue plus 3.0 g. of sodium hydroxide wasdissolved in 250 ml. of water, filtered, and stirred under argon at 25°C. for 36 hours. The solution was acidified to pH 4 1 N aqeous sulfuricacid, saturated with sodium chloride, and extracted with 5×200 ml. ofethyl ether. Evaporation of the ether solvent gave 10.42 g. of materialwhich upon purification by dry column chromatography over silica gelyielded 5.90 g. (87%) of7-{3alpha-(2-tetrahydropyranyloxy)-methyl-5alpha-hydroxy-2beta[4,4-dimethyl-3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-1-alpha-cyclopentyl}cis-5-heptenoicacid.

EXAMPLE 45 7[3 alpha-hydroxymethyl-5 alpha hydroxy-2 beta(4,4-dimethyl-3 alpha hydroxy-1-trans-octenyl)-1-alphacyclopentyl]-cis-5-heptenoic acid

By the procedure of Example 7, 7-{3alpha-(2-tetrahydropyranyloxy)methyl-5alpha-hydroxy-2-beta[4,4-dimethyl-3-alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-1-alpha-cyclopentyl}cis-5-heptenoicacid was converted to 7-[3 alpha-hydroxymethyl-5alpha-hydroxy-2-beta(4,4-dimethyl-3 alpha hydroxy-1-trans-octenyl)-1alpha cyclopentyl]-cis-5-heptenoic acid.

EXAMPLE 46 7-{3 alpha-(2-tetrahydropyranyloxy)methyl-5-oxo-2-beta[4,4-dimethyl-3 alpha (2-tetrahydropyranyloxy)-1-trans-octenyl]-1alpha-cyclopentyl}-cis-5-heptenoic acid.

By the procedure of Example 19, 7-{3alpha-(2-tetrahydropyranyloxy)methyl-5-alpha hydroxy-2 beta[4,4-dimethyl-3 alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-1-alpha-cyclopentyl}-cis-5-heptenoicacid was converted to 7-{3 alpha-(2-tetrahydropyranyloxy)methyl-5-oxo-2beta [4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-1-alpha-cyclopentyl}-cis-5-heptenoicacid.

EXAMPLE 47 7-[3 alpha-hydroxymethyl-5-oxo-2 beta (4,4-dimethyl-3 alphahydroxy-1-trans-octenyl)-1 alpha cyclopentyl]-cis-5-heptenoic acid

A mixture of 980 mg. of 7-{3 alpha-(2-tetrahydropyranyloxy)methyl-5-oxo-2 beta [4,4-dimethyl-3 alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-1 alphacyclopentyl}-cis-5-heptenoic acid and 90 ml. of 1:2 (v/v) glacial aceticacid water was agitated at 25° C. for 120 hours. The volatile componentswere removed at 35°-40° C./0.5 mmHg and the residue purified by columnchromatography over silica gel to yield 366 mg. (53%) of 7-[3alpha-hydroxymethyl-5-oxo-2 beta (4,4-dimethyl-3-alphahydroxy-1-trans-octenyl)-1 alpha cyclopentyl]-cis-5-heptenoic acid as aviscous oil.

EXAMPLE 48 Methyl 7-[3 alpha hydroxymethyl-5 alpha hydroxy-2 beta(4,4-dimethyl-3 alpha hydroxy-1-trans octenyl)-1 alphacyclopentyl]-cis-5-heptenoate

An etheral solution of 7-[3 alpha hydroxymethyl-5 alpha hydroxy-2 beta(4,4-dimethyl-3 alpha hydroxy-1-trans octenyl)-1 alpha cyclopentyl]cis-5-heptenoic acid was treated with a solution of diazomethane indiethyl ether until the yellow color persisted for more than 10 minutes.Evaporation of the solvent gave methyl 7-[3 alpha hydroxymethyl-5 alphahydroxy-2 beta (4,4-dimethyl-3-alpha hydroxy-1-trans octenyl)-1 alphacyclopentyl]-cis-5-heptenoate.

EXAMPLE 49 Methyl 7-[3 alpha hydroxymethyl-5-oxo-2 beta (4,4-dimethyl 3alpha hydroxy-1-trans-octenyl)-1 alpha cyclopentyl]-cis-5-heptenoate

By the procedure of Example 48, 7-[3 alpha hydroxymethyl-5-oxo-2 beta(4,4-dimethyl-3-alpha hydroxy-1-trans-octenyl)-1 alphacyclopentyl]-cis-5-heptenoic acid was converted into methyl 7-[3 alphahydroxymethyl-5-oxo-2 beta (4,4-dimethyl-3 alphahydroxy-1-trans-octenyl)-1 alpha cyclopentyl]-cis-5-heptenoate.m.p.=51°-52° C.

EXAMPLE 50 Methyl 7-{3 alpha-(2-tetrahydropyranyloxy)methyl-5 alphahydroxy 2 beta [4,4-dimethyl-3 alpha (2-tetrahydropyranyloxy)-1-transocetenyl]-1 alpha cyclopentyl} cis-5-heptenoate

By the procedure of Example 48, 7-[3alpha-(2-tetrahydropyranyloxy)methyl-5 alpha hydroxy 2 beta[4,4-dimethyl-3 alpha (2-tetrahydropyranyloxy)-1-trans octenyl]-1 alphacyclopentyl} cis-5-heptenoic acid was converted into methyl 7-{3alpha-(2-tetrahydropyranyloxy) methyl-5 alpha hydroxy-2-beta[4,4-dimethyl-3-alpha(2-tetrahydropyranyloxy)-1-trans octenyl]-1 alphacyclopentyl} cis-5-heptenoate.

EXAMPLE 51 Methyl 7-{3 alpha-(2-tetrahydropyranyloxy)methyl-5 oxo-2 beta[4,4-dimethyl-3 alpha (2-tetrahydropyranyloxy)-1-trans octenyl]-1alpha-cyclopentyl} cis-5-heptenoate

By the procedure of Example 19, methyl 7-{3alpha-(2-tetrahydropyranyloxy)methyl-5 alpha hydroxy-2 beta[4,4-dimethyl-3 alpha (2-tetrahydropyranyloxy)-1-trans-octenyl]-1alphacyclopentyl} cis-5-heptenoate was converted into methyl 7-{3alpha-(2-tetrahydropyranyloxy) methyl-5-oxo-2 beta [4,4-dimethyl-3 alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-1-alpha cyclopenyl}cis-5-heptenoate.

EXAMPLE 52

By the procedure of Example 47, methyl 7-{3alpha-(2-tetrahydropyranyloxy)methyl-5-oxo-2 beta [4,4-dimethyl-3-alpha(2-tetrahydropyranyloxy)-1-trans octenyl]-1alpha-cyclopentyl}cis-5-heptenoate is converted to methyl 7-{3alpha-hydroxymethyl-5 alpha oxo-2 beta [4,4-dimethyl-3alpha-hydroxy-1-trans-octenyl]-1 alpha cyclopentyl} cis-5-heptenoate.

EXAMPLE 53 11-homo-prostaglandin F₂α, 11 a, 15-bis (2-tetrahydropyranylether) methyl ester

By the procedure of Example 48, 11-homo-prostaglandin F₂α, 11a,15-bis-(2-tetrahydropyranyl ether) was converted to 11-homoprostaglandin F₂α, 11a, 15-bis(2-tetrahydropyranyl ether) methyl ester.

EXAMPLE 54 11-homo-prostaglandin E₂, 11a, 15-bis-(2-tetrahydropyranylether) methyl ester

By the procedure of Example 19, 11-homo-prostaglandin F₂α, 11a, 15-bis(2-tetrahydropyranyl ether) methyl ester was converted to11-homo-prostaglandin E₂ 11a, 15-bis-(2-tetrahydropyranyl ether) methylester.

EXAMPLE 55 11-homo-prostaglandin F₂α methyl ester

By the procedure of Example 18, 11-homo-prostaglandin F₂α 11a,15-bis(2-tetrahydropyranyl ether) methyl ester was hydrolyzed to11-homo-prostaglandin F₂α methyl ester.

EXAMPLE 56 11-homo-prostaglandin E₂ methyl ester

By the procedure of Example 18, 11-homo-prostaglandin E₂ 11a, 15-bis(2-tetrahydropyranyl ether) methyl ester was converted to11-homo-prostaglandin E₂ methyl ester.

EXAMPLE 57

By the procedure of Example 21, lithium dimethyl methyl phosphonate wasreacted with 2-methyl-2-fluoroethyl hexanoate to produce dimethyl(-2-oxo-3-methyl-3-fluoroheptyl)-phosphonate b.p. 106° C./0.2 mmHg.

EXAMPLE 58

To a suspension of 0.72 g. of sodium hydride in 150 ml. of dry glyme wasadded 6 g. of dimethyl (2-oxo-3-fluoroheptyl) phosphonate. Afterstirring for 1.5 hour, 5 g. of3,3abeta-4,5,6,6abeta-hexahydro-4beta-formyl-5alpha-methyl-2-oxo-2H-cyclopenta[b] furan dissolved in 30 ml. of glyme was added dropwise at 0° C. Afterstirring for 3 hours at room temperature, 500 ml. of diethyl ether wasadded and the mixture was washed with water. The organic layer was thendried (MgSO₄) and the solvent removed under reduced pressure. Theresidue was then washed through 75 g. of silica gel to give 7.1 g. of3,3abeta-4,5,6,6abeta-hexahydro-4beta-(3-oxo-4-fluoro-1-trans-octenyl)-5alpha-methyl-2-oxo-2H-cyclopenta[b] furan. CL EXAMPLE 59

By the procedure of Example 58,3,3abeta-4,5,6,6abeta-hexahydro-4beta-formyl-5alpha-methyl-2-oxo-2H-cyclopenta[b] furan was reacted with dimethyl (2-oxo-3-methyl-3-fluoroheptyl)phosphonate to give 3,3abeta,4,5,6,6abeta-hexahydro-4beta(3-oxo-4-methyl-4-fluoro-1-trans-octenyl) 5alpha-methyl-2-oxo-2H-cyclopenta [b] furan.

EXAMPLE 60

By the procedure of Example 58, 3,3abeta4,5,6,6abeta-hexahydro-4beta-formyl-5alpha-methyl-2-oxo-2H-cyclopenta[b] furan was reacted with dimethyl-(2-oxo-3,3-dimethyl heptyl)phosphonate to give3,3abeta,4,5,6,6abeta-hexahydro-4-beta(3-oxo-4,4-dimethyl-1-trans-octenyl)5alpha-methyl-2-oxo-2H-cyclopenta [b] furan.

EXAMPLE 61

To a solution of 4.5 g. of3,3abeta-4,5,6,6abeta-hexahydro-4beta-(3-oxo-4-fluoro-1-trans-octenyl)-5alpha-methyl-2-oxo-2H-cyclopenta[b] furan in 100 ml. of dry glyme was added an excess of zincborohydride in 50 ml. of glyme and the resulting solution stirred for 3hours. The solution was cooled to 0° C. and treated with 200 ml. ofwater, 400 ml. of ether and 10 ml. of 0.5 N aqueous sulfuric acid. Theether was separated and dried (MgSO₄) and the solvent removed underreduced pressure to give 3,3abeta-4,5,6,6abeta-hexahydro-4beta-(3-hydroxy-4-fluoro-1-trans-octenyl)-5alpha-methyl-2-oxo-2H-cyclopenta[b] furan. Column chromatography on silica gel utilizing diethyl etherhexane (70:30 parts by volume) then afforded first the3,3abeta-4,5,6,6abeta-hexahydro-4beta-(3alpha-hydroxy-4-fluoro-1-trans-octenyl)-5alphamethyl-2-oxo-2H-cyclopenta[b]furanand then3,3abeta-4,5,6,6abeta-hexahydro-4beta-(3beta-hydroxy-4-fluoro-1-trans-octenyl)-5 alpha-methyl-2-oxo-2H-cyclopenta [b] furan.

EXAMPLE 62

By the procedure of Example 61,3,3abeta-4,5,6,6abeta-hexahydro-4alpha-(3-oxo-4-fluoro-4-methyl-1-trans-octenyl)-5alphamethyl-2-oxo-2H-cyclopenta [b] furan was converted to 3,3abeta-4,5,6,6abeta-hexahydro-4beta(3alpha-hydroxy-4-fluoro-4-methyl-1-trans-octenyl)-5alphamethyl-2-oxo-2H-cyclopenta [b] furan and 3,3abeta,4,5,6,6abeta-hexahydro-4 beta (3beta-hydroxy-4-fluoro-4-methyl-1-trans-octenyl)-3 alphamethyl-2-oxo-2H-cyclopenta[b]furan which were separated by columnchromatography in the manner of Example 61.

EXAMPLE 63

By the procedure of Example 61,3,3abeta,4,5,6,6abeta-hexahydro-4-beta-(3-oxo-4,4-dimethyl-1-trans-octenyl)-5alpha-methyl-2-oxo-2H-cyclopenta[b]furanwas converted to 3,3abeta,4,5,6,6abetahexahydro-4-beta(3alpha-hydroxy-4,4-dimethyl-1-trans-octenyl)-5alpha-methyl-2-oxo-2H-cyclopenta[b]furanand 3,3abeta,5,5,6,6abeta-hexahydro-4-beta (3beta-hydroxy-4,4-dimethyl-1-trans-octenyl)-5 alphamethyl-2-oxo-2H-cyclopenta[b]furan which was separated by columnchromatography in the manner of Example 61.

EXAMPLE 64

A solution of 5 g. of3,3abeta-4,5,6,6abeta-hexahydro-4-beta-(3alpha-hydroxy-4-fluoro-1-trans-octenyl)-5alpha-methyl-2-oxo-2H-cyclopenta[b]furan.12 g. of dihydropyran and 25 mg. of p-toluene sulfonic acid in 200 ml.of methylene chloride was stirred at 25° C. for 3 hours. The solutionwas washed with saturated sodium bicarbonate solution, the methylenechloride solution dried (MgSO₄) and the volatile components evaporatedunder reduced pressure to give 6.4 g. of3,3abeta-4,5,6,6abeta-hexahydro-4beta[3alpha(2-tetrahydropyranyloxy)-4-fluoro-1-trans-octenyl]5alpha-methyl-2-oxo-2H-cyclopent[b]furan.

EXAMPLE 65

By the procedure of Example 64,3,3abeta-4,5,6,6abeta-hexahydro-4-beta-(3alpha-hydroxy-4-fluoro-4-methyl-1-trans-octenyl)-5alphamethyl-2-oxo-2H-cyclopenta[b]furan was converted to3,3abeta,4,5,6,6abeta-hexahydro-4beta[3-alpha-(2-tetrahydropyranyloxy)-4-fluoro-4-methyl-1-trans-octenyl]-5-alphamethyl-2-oxo-2H-cyclopenta[b]furan.

EXAMPLE 66

By the procedure of Example 64, 3,3abeta,4,5,6,6abeta-hexahydro-4beta-(3alpha-hydroxy-4,4-dimethyl-1-trans-octenyl)5 alpha-methyl-2H-cyclopenta[b]furan is converted to3,3abeta,4,5,6,6abeta-hexahydro-4beta-[3alpha(2-tetrahydropyranyloxy)-4,4-dimethyl-1-trans-octenyl]-5alpha-methyl-2H-cyclopenta[b]furan.

EXAMPLE 67

To a solution of 5.3 g. of3,3abeta-4,5,6,6abeta-hexahydro-4beta-[3alpha(2tetrahydropyranyloxy)-4-fluoro-1-trans-octenyl]5alpha-methyl-2-oxo-2H-cyclopenta[b]furanin 150 ml. of toluene, was added dropwise at -78° C., 1 equivalent ofdiisobutylaluminum hydride in the same solvent. The reaction mixture wasstirred at this temperature for 2 hours after which time 20 ml. ofmethanol was slowly added and the mixture stirred for 2 hours at roomtemperature. The mixture was then filtered thru a bed of charcoal, thecharcoal was washed with ethyl acetate and the solvents were thenremoved under reduced pressure. The residue was then washed thru acolumn of silica gel to give 3,3abeta-4,5,6,6abeta-hexahydro-4beta[3alpha(2-tetrahydropyranyloxy)-4-fluoro-1-trans-octenyl]5alpha-methyl-2H-cyclopenta[b]furan-2-ol.

EXAMPLE 68

By the procedure of Example 67,3,3abeta-4,5,6,6abeta-hexahydro-4beta-[3alpha(2-tetrahydropyranyloxy)-4-fluoro-4-methyl-1-trans-octenyl]-5alpha-methyl-2-oxo-2H-cyclopenta[b]furanwas converted to 3,3abeta-4,5,6,6abeta-hexahydro-4beta[3alpha(2-tetrahydropyranyloxy)-4-fluoro-4-methyl-1-trans-octenyl]-5-alpha-methyl-2H-cyclopenta[b]furan-2-ol.

EXAMPLE 69

By the procedure of Example 67, 3,3abeta-4,5,6,6abeta-hexahydro-4beta[3alpha (2-tetrahydropyranyloxy)-4,4-dimethyl-1-trans-octenyl]-5 alphamethyl-2-oxo-2H-cyclopenta[b]furan was converted to3,3abeta-4,5,6,6abeta-hexahydro-4beta[3 alpha(2-tetrahydropyranyloxy)-4,4-dimethyl-1-trans-octenyl]-5-alphamethyl-2H-cyclopenta[b]furan-2-ol.

EXAMPLE 70

3.2 g. (8.6 mmol) of 3,3abeta,4,5,6,6abeta-hexahydro-4beta[3alpha-(2-tetrahydropyranyloxy)-4-fluoro-1-trans-octenyl]5alpha-methyl-2H-cyclopenta[b]furan-2-olin 150 ml. of hexamethylphosphoric triamide was reacted with 2.2equivalents of Wittig reagent generated by the reaction of 7.0 g.(0.0384 mol) of sodium bis-trimethylsilyl amide with 8.4 g. (0.019 mol)of (4-carboxybutyl)-tri-phenylphosphonium bromide. After stirring forthirty minutes, the hexamethylphosphoramide was removed under highvacuum. The residue was treated with 1 N sodium hydroxide and themixture was stirred for 2 hours at room temperature. The mixture wasthen extracted with ether and the water layer separated and cautiouslyacidified. The aqueous mixture was then extracted with ether. The ethersolution dried (Na₂ SO₄) and the solvent removed under reduced pressure.The residue was then chromatographed on silica gel to give 3.5 g. of7-(3alpha-methyl-5alpha-hydroxy-2beta[3alpha-(2-tetrahydropyranyloxy)-4-fluoro-1-trans-octenyl]-1-alpha-cyclopentyl)-cis-5-heptanoicacid.

EXAMPLE 71

By the procedure of Example 70,3,3abeta,4,5,6,6abeta-hexahydro-4beta[3alpha(2-tetrahydropyranyloxy)-4-fluoro-4-methyl-1-trans-octenyl]-5alphamethyl-2H-cyclopenta[b]furan-2-ol is converted to7{3alpha-methyl-5alpha-hydroxhy-2beta[3alpha-(2-tetrahydropyranyloxy)-4-fluoro-4-methyl-1-trans-octenyl]-1-alpha-cyclopentyl}-cis-5-heptenoicacid.

EXAMPLE 72

By the procedure of Example 70,3,3abeta,4,5,6,6abeta-hexahydro-4beta[3alpha(2-tetrahydropyranyloxy)-4,4-dimethyl-1-trans-octenyl]-5alphamethyl-2H-cyclopenta[b]furan-2-ol is converted to7{3-alpha-methyl-5alpha-hydroxy-2beta[3alpha-(2-tetrahydropyranyloxy)-4,4-dimethyl-1-trans-octenyl]-1-alpha-cyclopentyl}-cis-5-heptenoicacid.

EXAMPLE 73

To a mixture of 6 g. of chromium trioxide and 9.5 g. of pyridine in 150ml. of methylene chloride was added at 0° C. 4.5 g. of7{3-alpha-methyl-5alpha-hydroxy-2beta[3alpha-(2-tetrahydropyranyloxy)-4-fluoro-1-trans-octenyl]1-alpha-cyclopentyl}-cis-5-heptenoicacid dissolved in 50 ml. of methylene chloride. The mixture was stirredfor 1 hour at room temperature and the mixture filtered thru a bed ofcelite. The celite was washed with methylene chloride and the combinedmethylene chloride solution washed with dilute hydrochloric acid toremove any remaining pyridine. The methylene chloride was then removedunder reduced pressure and the residue treated with 50 ml. of 3:1 partsby volume acetic acid/water solution at 35° C. for 15 hours. Thesolvents were then removed under high vacuum and the residue purified bycolumn chromatography to give7-[3alpha-methyl-5-oxo-2beta(3alpha-hydroxy-4-fluoro-1-trans-octenyl)-1-alpha-cyclopentyl]cis-5-heptenoicacid.

EXAMPLE 74

By the procedure of Example 73,7-{3-alpha-methyl-5-alpha-hydroxy-2beta[3alpha-(2-tetrahydropyranyloxy)-4-fluoro-4-methyl-1-trans-octenyl]1-alpha-cyclopentyl}-cis-5-heptenoicacid was converted to7[-3-alpha-methyl-5-oxo-2beta(3alpha-hydroxy-4-fluoro-4-methyl-1-trans-octenyl)-1-alpha-cyclopentyl]cis-5-heptenoicacid.

EXAMPLE 75

By the procedure of Example 73, 7{3 alphamethyl-5-alpha-hydroxy-2beta[3alpha-(2-tetrahydropyranyloxy)-4,4-dimethyl-1-trans-octenyl]-1-alpha-cyclopentyl}-cis-5-heptenoicacid was converted to 7[3-alpha methyl-5-oxo-2beta(3alpha-hydroxy-4,4-dimethyl-1-trans-octenyl)1-alpha-cyclopentyl]cis-5-heptenoicacid.

EXAMPLE 76

A solution of 200 mg. of7-{3alpha-methyl-5alpha-hydroxy-2beta[3alpha-(2-tetrahydropyranyloxy)-4-fluoro-1-trans-octenyl]-1-alpha-cyclopentyl}-cis-5-heptenoicacid in 5 ml. of 3:1 parts by volume acetic acid/water solution was keptat 35° C. for 15 hours. The solvent was then removed under high vacuumand the residue purified via column chromatography to give7[3-alpha-methyl-5alpha-hydroxy-2beta(3alpha-hydroxy-4-fluoro-1-trans-octenyl)-1-alpha-cyclopentyl]cis-5-heptenoicacid.

EXAMPLE 77

By the procedure of Example 76,7{3-alpha-methyl-5alpha-hydroxy-2beta[3alpha-(2-tetrahydropyranyloxy)-4-fluoro-4-methyl-1-trans-octenyl]-1-alpha-cyclopentyl}-cis-5-heptenoicacid was converted to7[3-alpha-methyl-5alpha-hydroxy-2beta(3alpha-hydroxy-4-fluoro-4-methyl-1-trans-octenyl)-1-alpha-cyclopentyl]cis-5-heptenoicacid.

EXAMPLE 78

By the procedure of Example 76, 7{3-alphamethyl-5alpha-hydroxy-2beta[3alpha-(2-tetrahydropyranyloxy)-4,4-dimethyl-1-trans-octenyl]-1-alpha-cyclopentyl}-cis-5-heptenoicacid was converted to 7[3-alpha-methyl-5-alpha-hydroxy-2beta(3alpha-hydroxy-4,4-dimethyl-1-trans-octenyl)-1-alpha-cyclopentyl]-cis-5-heptenoicacid.

EXAMPLE 79

By the procedure of Example 58, dimethyl (2-oxo-3-fluoroheptyl)phosphonate was reacted with3,3abeta,4,5,6,6abeta-hexahydro-4beta-formyl-2-oxo-2H-cyclopenta[b]furanto produce3,3abeta,4,5,6,6abeta-hexahydro-4beta-(3-oxo-4-fluoro-1-trans-octenyl)-2-oxo-2H-cyclopenta[b]furan.

EXAMPLE 80

By the procedure of Example 58,3,3abeta-4,5,6-abeta-hexahydro-4beta-formyl-2-oxo-2H-cyclopenta[b]furanwas reacted with dimethyl (2-oxo-3-methyl-3-fluoroheptyl) phosphonate togive 3,3abeta,4,5,6,6abeta-hexahydro-4beta(3-oxo-4-methyl-4-fluoro-1-trans-octenyl)-2-oxo-2H-cyclopenta[b]furan.

EXAMPLE 81

By the procedure of Example 58,3,3abeta,4,5,6,6abeta-hexahydro-4beta-formyl-2-oxo-2H-cyclopenta[b]furanwas reacted with dimethyl-(2-oxo-3,3-dimethyl heptyl) phosphonate togive3,3abeta,4,5,6,6abeta-hexahydro-4-beta(3-oxo-4,4-dimethyl-1-trans-octenyl)-2-oxo-2H-cyclopenta[b]furan.

EXAMPLE 82

By the procedure of Example 61,3,3abeta,4,5,6,6abeta-hexahydro-4beta-(3-oxo-4-fluoro-1-trans-octenyl)-2-oxo-2H-cyclopenta[b]furanwas reacted to give3,3abeta,4,5,6,6abeta-hexahydro-4beta-(3-hydroxy-4-fluoro-1-trans-octenyl)-2-oxo-2H-cyclopenta[b]furan.Chromatography on silica gel in the manner of Example 61 afforded firstthe3,3abeta,4,5,6,6abeta-hexahydro-4beta-(3alpha-hydroxy-4-fluoro-1-trans-octenyl)-2-oxo-2H-cyclopenta[b]furan.Also obtained by chromatography was the3,3abeta,4,5,6,6abeta-hexahydro-4beta(3beta-hydroxy-4-fluoro-1-trans-octenyl)-2-oxo-2H-cyclopenta[b]furan.

EXAMPLE 83

By the procedure of Example 61,3,3abeta,4,5,6,6abeta-hexahydro-4beta-(3-oxo-4-fluoro-4-methyl-1-trans-octenyl)-2-oxo-2H-cyclopenta[b]furanwas converted to3,3abeta,4,5,6,6abeta-hexahydro-4beta-(3alpha-hydroxy-4-fluoro-4-methyl-1-trans-octenyl)-2-oxo-2H-cyclopenta[b]furanand3,3abeta,4,5,6,6abeta-hexahydro-4beta(3beta-hydroxy-4-fluoro-4-methyl-1-trans-octenyl)-2-oxo-2H-cyclopenta[b]furanwhich were separated by column chromatography in the manner of Example61.

EXAMPLE 84

By the procedure of Example 61,3,3abeta,4,5,6,6abeta-hexahydro-4-beta-(3-oxo-4,4-dimethyl-1-trans-octenyl)-2-oxo-2H-cyclopenta[b]furanwas converted to 3,3abeta,4,5,6,6abetahexahydro-4-beta(3alpha-hydroxy-4,4-dimethyl-1-trans-octenyl)-2-oxo-2H-cyclopenta[b]furanand3,3abeta,4,5,6,6abeta-hexahydro-4-beta-(3-beta-hydroxy-4,4-dimethyl-1-trans-octenyl)-2-oxo-2H-cyclopenta[b]furanwhich were separated by chromatography in the manner of Example 61.

EXAMPLE 85

By the procedure of Example 64,3,3abeta-4,5,6,6abeta-hexahydro-4beta-[3alpha-hydroxy-4-fluoro-1-trans-octenyl]-2-oxo-2H-cyclopenta[b]furanwas converted to3,3abeta,4,5,6,6abeta-hexahydro-4beta[3alpha(2-tetrahydropyranyloxy)-4-fluoro-1-trans-octenyl]-2-oxo-2H-cyclopenta[b]furan.

EXAMPLE 86

By the procedure of Example 64,3,3abeta,4,5,6,6abeta-hexahydro-4beta-(3alpha-hydroxy-4-fluoro-4-methyl-1-trans-octenyl)-2-oxo-2H-cyclopenta[b]furanwas converted to3,3abeta,4,5,6,6abeta-hexahydro-4beta[3alpha-(2-tetrahydropyranyloxy)-4-fluoro-4-methyl-1-trans-octenyl]-2-oxo-2H-cyclopenta[b]furan.

EXAMPLE 87

By the procedure of Example 64,3,3abeta,4,5,6,6abeta-hexahydro-4beta-(3alpha-hydroxy-4,4-dimethyl-1-trans-octenyl)-2H-cyclopenta[b]furan-2-oneis converted to3,3abeta,4,5,6,6abeta-hexahydro-4beta-[3alpha(2-tetrahydropyranyloxy)-4,4-dimethyl-1-trans-octenyl]-2H-cyclopenta[b]furan-2-one.

EXAMPLE 88

By the procedure of Example 67,3,3abeta,4,5,6,6abeta-hexahydro-4beta-[3alpha(2-tetrahydropyranyloxy)-4-fluoro-1-trans-octenyl]-2-oxo-2H-cyclopenta[b]furanis converted to3,3abeta,4,5,6,6abeta-hexahydro-4beta[3alpha(2-tetrahydropyranyloxy)-4-fluoro-1-trans-octenyl]-2H-cyclopenta[b]furan-2-ol.

EXAMPLE 89

By the procedure of Example 67,3,3abeta,4,5,6,6abeta-hexahydro-4beta-[3alpha(2-tetrahydropyranyloxy)-4-fluoro-4-methyl-1-trans-octenyl]-2-oxo-2H-cyclopenta[b]furanwas converted to3,3abeta,4,5,6,6abeta-hexahydro-4beta[3alpha(2-tetrahydropyranyloxy)-4-fluoro-4-methyl-1-trans-octenyl]-2H-cyclopenta[b]furan-2-ol.

EXAMPLE 90

By the procedure of Example 67,3,3abeta,4,5,6,6abeta-hexahydro-4beta-[3alpha(2-tetrahydropyranyloxy)-4,4-dimethyl-1-trans-octenyl]-2-oxo-2H-cyclopenta[b]furanwas converted to3,3abeta,4,5,6,6abeta-hexahydro-4beta[3alpha(2-tetrahydropyranyloxy)-4,4-dimethyl-1-trans-octenyl]-2H-cyclopenta[b]furan-2-ol.

EXAMPLE 91

By the procedure of Example 70,3,3abeta,4,5,6,6abeta-hexahydro-4beta[3alpha-(2-tetrahydropyranyloxy)-4-fluoro-1-trans-ocentyl]-2H-cyclopenta[b]furan-2-olwas converted to7-(5alpha-hydroxy-2-beta[3-alpha-(2-tetrahydropyranyloxy)-4-fluoro-1-trans-octenyl]-1-alphacyclopentyl)-cis-5-heptenoicacid.

EXAMPLE 92

By the procedure of Example 70,3,3abeta,4,5,6,6abeta-hexahydro-4beta[3alpha(2-tetrahydropyranyloxy)-4-fluoro-4-methyl-1-trans-octenyl]-2H-cyclopenta[b]furan-2-olwas converted to7{5-alpha-hydroxy-2beta[3alpha-(2-tetrahydropyranyloxy)-4-fluoro-4-methyl-1-trans-octenyl]-1-alpha-cyclopentyl}-cis-5-heptenoicacid.

EXAMPLE 93

By the procedure of Example 70,3,3abeta,4,5,6,6abeta-hexahydro-4beta[3alpha(2-tetrahydropyranyloxy)4,4-dimethyl-1-trans-octenyl]-2H-cyclopenta[b]furan-2-olwas converted to7{5-alpha-hydroxy-2beta[3alpha-(2-tetrahydropyranyloxy)-4,4-dimethyl-1-trans-octenyl]-1-alpha-cyclopentyl}-cis-5-heptenoicacid.

EXAMPLE 94

By the procedure of Example 73,7{5alpha-hydroxy-2beta[3alpha-(2-tetrahydropyranyloxy)-4-fluoro-1-trans-octenyl]-1-alpha-cyclopentyl}cis-5-heptenoicacid was converted to7{5-oxo-2beta(3alpha-hydroxy-4-fluoro-1-trans-octenyl)-1-alpha-cyclopentyl}cis-5-heptenoicacid.

EXAMPLE 95

By the procedure of Example 73,7{5-alpha-hydroxy-2beta[3alpha-(2-tetrahydropyranyloxy)-4-fluoro-4-methyl-1-trans-octenyl]-1-alpha-cyclopentyl}-cis-5-heptenoicacid was converted to7[5-oxo-2beta(3alpha-hydroxy-4-fluoro-4-methyl-1-trans-octenyl)-1-alpha-cyclopentyl]cis-5-heptenoicacid.

EXAMPLE 96

By the procedure of Example 73,7{5-alpha-hydroxy-2beta-[3alpha-(2-tetrahydropyranyloxy)-4,4-dimethyl-1-trans-octenyl]-1-alpha-cyclopentyl}-cis-5-heptenoicacid was converted to7[5-oxo-2beta(3alpha-hydroxy-4,4-dimethyl-1-trans-octenyl)-1-alpha-cyclopentyl]cis-5-heptenoicacid.

EXAMPLE 97

A solution of 200 mg. of7-{5alpha-hydroxy-2beta[3alpha-(2-tetrahydropyranyloxy-4-fluoro-1-trans-octenyl]-1-alpha-cyclopentyl}-cis-5-heptenoicacid in 5 ml. of a 3:1 parts by volume acetic acid/water solution waskept at 35° C. for 15 hours. The solvent was then removed under highvacuum and the residue purified via column chromatography to give7[5alpha-hydroxy-2beta(3alpha-hydroxy-4-fluoro-1-trans-octenyl)-1-alpha-cyclopentyl]-cis-5-heptenoicacid.

EXAMPLE 98

By the procedure of Example 73,7{5alpha-hydroxy-2beta[3alpha-(2-tetrahydropyranyloxy)-4-fluoro-4-methyl-1-trans-octenyl]-1-alpha-cyclopentyl}cis-5-heptenoicacid was converted to7[5-oxo-2beta-(3alpha-hydroxy-4-fluoro-4-methyl-1-trans-octenyl)-1-alpha-cyclopentyl]cis-5-heptenoicacid.

EXAMPLE 99

By the procedure of Example 73,7{5alpha-hydroxy-2beta-[3alpha-(2-tetrahydropyranyloxy)-4,4-dimethyl-1-trans-octenyl]-1-alpha-cyclopentyl}-cis-5-heptenoicacid was converted to7[5-oxo-2beta(3alpha-hydroxy-4,4-dimethyl-1-trans-octenyl)-1-alpha-cyclopentyl]cis-5-heptenoicacid.

EXAMPLE 1003,3abeta,4,5,6,6abeta-hexahydro-4beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alphamethoxy methyl-2H-cyclopenta[b]furan-2-one.

A solution of 5.5 g. of3,3abeta,4,5,6,6abeta-hexahydro-4beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alphahydroxymethyl-2H-cyclopenta[b]furan-2-one in 10 ml. of dimethoxyethanewas added dropwise to a stirred slurry of 0.34 g. of sodium hydride in40 ml. of dimethoxyethane. After ten minutes, 2.0 g. of methyl iodidewas added and the mixture was stirred for two hours. The mixture wasthen diluted with 100 ml. of diethyl ether and 50 ml. of hexane, washedwith saturated aqueous sodium chloride solution, dried (MgSO₄) and thesolvent evaporated to yield 5.45 g. of crude3,3abeta,4,5,6,6abeta-hexahydro-4beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alphamethoxymethyl-2H-cyclopenta[b]furan-2-one which was purified by drycolumn chromatography over silica gel.

EXAMPLE 1013,3abeta,4,5,6,6abeta-hexahydro-4beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)1-trans-octenyl]5alphamethoxymethyl-2H-cyclopenta[b]furan-2-ol

By the procedure of Example 2,3,3abeta,4,5,6,6abeta-hexahydro-4beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]5alphamethoxymethyl-2H-cyclopenta[b]furan-2-one was reduced withbis-3-methyl-2-butylborane in tetrahydrofuran to3,3abeta,4,5,6,6abeta-hexahydro-4beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alphamethoxymethyl-2H-cyclopenta[b]furan-2-ol.

EXAMPLE 102 methyl7-{2beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-3alphamethoxymethyl-5alpha hydroxy-1alpha cyclopentyl}-cis-5-heptenoate

By the procedure of Example 3,3,3abeta,4,5,6,6abeta-hexahydro-4beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alphamethoxymethyl-2H-cyclopenta[b]furan-2-ol was converted in hexamethylphosphoramide with the Wittig reagent derived from(4-carboxybutyl)triphenylphosphonium bromide to7-{2beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)1-trans-octenyl]-3alphamethoxymethyl-5alpha hydroxy-1alpha-cyclopentyl}cis-5-heptenoic acid,which when treated with 1.1 equivalent of diazomethane in ethyl ethergave methyl7-{2beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)1-trans-octenyl]3alphamethoxymethyl-5alpha hydroxy-1alpha cyclopentyl}-cis-5-heptenoate.

EXAMPLE 103 methyl 7-{2beta(4,4-dimethyl-3alphahydroxy-1-trans-octenyl)3alpha methoxymethyl-5alpha hydroxy-1alphacyclopentyl}cis-5-heptenoate

A solution of 400 mg. of7-{2beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)1-trans-octenyl]-3alphamethoxymethyl-5alpha hydroxy-1alpha cyclopentyl}cis-5-heptenoic acid in50 ml. of a mixture of acetic acid, water and acetonitrile (2:1:4) waswarmed at 37° C. for 15 hours. Evaporation of the solvent followed bypurification by column chromatography over silica gel yielded 274 mg. of7-{2beta(4,4-dimethyl-3alpha-hydroxy-1-trans-octenyl)-3alphamethoxymethyl-5alpha hydroxy-1alpha cyclopentyl}-cis-5-heptenoic acidwhich was converted to methyl7-{2beta(4,4-dimethyl-3alpha-hydroxy-1-trans-octenyl)-3alphamethoxymethyl-5alpha hydroxy-1alpha cyclopentyl}-cis-5-heptenoate byreaction with etheral diazomethane.

EXAMPLE 104 methyl 7-{2beta(4,4-dimethyl-3alphahydroxy-1-trans-octenyl)-3alpha methoxymethyl-5-oxo-1alphacyclopentyl}-cis-5-heptenoate

A solution of methyl7-{2beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-3alphamethoxymethyl-5alpha hydroxy-1alpha cyclopentyl}-cis-5-heptenoate (1.0g.) in 5 ml. of methylene chloride was mixed with a solution of 1.75 g.of pyridine and 1.1 g. of chromium trioxide in 30 ml. of methylenechloride. After thirty minutes, the mixture was diluted with 100 ml. ofethyl ether and successively washed with 0.5 M sodium hydroxide, 0.5 Nsulfuric acid, and 5% sodium bicarbonate, dried (MgSO₄) and the solventevaporated to give 0.98 g. of crude methyl7-{2beta[4,4-dimethyl-3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-3alphamethoxymethyl-5-oxo-1alpha cyclopentyl}cis-5-heptenoate which washydrolyzed to methyl 7-{2beta(4,4-dimethyl-3alphahydroxy-1-trans-octenyl)-3alpha methoxymethyl-5-oxo-1alphacyclopentyl}cis-5-heptenoate in 100 ml. of a mixture of acetic acid,water and acetonitrite (1:1:2) at 37°-40° C.

EXAMPLE 105 7-{2beta(4,4-dimethyl-3alpha hydroxy-1-trans-octenyl)-3alphamethoxymethyl-5-oxo-1alpha cyclopentyl}cis-5-heptenoic acid

A solution of 66 mg. of methyl 7-{2beta(4,4-dimethyl-3alphahydroxy-1-trans-octenyl)-3alpha methoxymethyl-5-oxo-1alphacyclopentyl}cis-5-heptenoate in 20 ml. of methanol and 2 ml. of 6%sodium hydroxide was warmed to 37°-40° C. for 10 hours. Most of themethanol was evaporated at reduced pressure and the residue acidified topH 3 with 0.5 N sulfuric acid, saturated with sodium chloride, andextracted with ethyl acetate. Evaporation of the dried (MgSO₄) ethylacetate extract yielded 45 mg. of 7-{2beta(4,4-dimethyl-3alphahydroxy-1-trans-octenyl)-3alpha methoxymethyl-5-oxo-1alphacyclopentyl}-cis-5-heptenoic acid which was purified by columnchromatography over silica gel.

EXAMPLE 106 7-[3alpha carbomethoxy-5-oxo-2beta(3betahydroxy-1-trans-octenyl)-1alpha cyclopentyl]-cis-5-heptenoic acid

By the procedure of Example 1, 3,3abeta,4,5,6,6abeta-4beta(3betahydroxy-1trans-octenyl)-5alpha carbomethoxy-2-oxo-2H-cyclopenta[b]-furanwas converted to3,3abeta,4,5,6,6abeta-hexahydro-4beta[3beta(2-tetrahydropyranyloxy)-1-trans-octenyl]-5-alpha-carbomethoxy-2-oxo-2H-cyclopenta[b]furan;m.p. 55°-57° C., which was converted by the procedure of Example 2 togive3,3abeta,4,5,6,6abeta-hexahydro-4beta[3beta(2-tetrahydropyranyloxy)-1-trans-octenyl]-5-alphacarbomethoxy-2H-cyclopenta[b]furan-2-ol which was converted by theprocedure of Example 3 to 7-{3alphacarbomethoxy-5alpha-hydroxy-2beta[3beta(2tetrahydropyranyloxy)-1-trans-octenyl]-1-alphacyclopentyl}-cis-5-heptenoic acid which upon hydrolysis by the procedureof Example 7 gave 7-[3alpha carbomethoxy-5alphahydroxy-2beta(3beta-hydroxy-1-trans-octenyl)-1-alphacyclopentyl]-cis-5-heptenoic acid. Alternatively, oxidation by theprocedure of Example 19 gave 7-{3alphacarbomethoxy-5-oxo-2beta[3beta(2-tetrahydropyranyloxy)-1-trans-octenyl]-1-alpha cyclopentyl}-cis-5-heptenoic acid which washydrolyzed by the procedure of Example 7 to 7-[3alphacarbomethoxy-5-oxo-2beta(3beta hydroxy-1-trans-octenyl)-1alphacyclopentyl]-cis-5-heptenoic acid.

EXAMPLE 107

By the procedures described in Examples 64,67, 70, 73 and 76,3,3abeta-4,5,6,6abeta-hexahydro-4beta(3beta-hydroxy-4-fluoro-1-trans-octenyl)5alpha-methyl-2-oxo-2H-cyclopenta[b]furanwas converted to the following compounds:

1.3,3abeta-4,5,6,6abeta-hexahydro-4beta[3beta(2-tetrahydropyranyloxy)-4-fluoro-1-trans-octenyl5alpha-methyl-2-oxo-2H-cyclopenta[b]furan.

2.3,3abeta-4,5,6,6abeta-hexahydro-4beta[3beta(2-tetrahydropyranyloxy)-4fluoro-1-trans-octenyl]5alpha-methyl-2H-cyclopenta[b]furan-2-ol.

3.7-{3alpha-methyl-5alpha-hydroxy-2beta[3beta(2-tetrahydropyranyloxy)-4-fluoro-1-trans-octenyl]1alpha-cyclopentyl}cis-5-heptenoicacid.

4.7[3alpha-methyl-5-oxo-2beta(3beta-hydroxy-4-fluoro-1-trans-octenyl)1alpha-cyclopentyl]cis-5-heptenoicacid.

5.7[3alpha-methyl-5alpha-hydroxy-2beta(3beta-hydroxy-4-fluoro-1-trans-octenyl)1alpha-cyclopentyl]cis-5-heptenoicacid.

EXAMPLE 108

A tablet was found containing the following ingredients:

    ______________________________________                                                               Per Tablet                                             ______________________________________                                        7-[3 alpha-methyl-5-oxo-2 beta-(3 alpha-hydroxy-                                                       200     mg.                                          4-fluoro-1-trans-octenyl)-1 alpha-cyclopentyl]-                               cis-5-heptenoic acid                                                          Dicalcium Phosphate Dihydrate, Unmilled                                                                235     mg.                                          Corn Starch              70      mg.                                          FD&C Yellow #5 - Aluminum Lake 25%                                                                     2       mg.                                          Durkee Duratex*          25      mg.                                          Calcium Stearate         3       mg.                                          TOTAL Weight             535     mg.                                          ______________________________________                                         *Hydrogenated Cotton Seed Oil (Fully Saturated).                         

All of the above ingredients were mixed until thoroughly blended in asuitable size container. The powder was filled into #2, two-piece, hardshell gelatin capsules to an approximate fill weight of 350 mg. using acapsulating machine.

EXAMPLE 109

A capsule was prepared by the procedure of Example 108 except that7-[2-beta-(4,4-dimethyl-3-alpha-hydroxy-1-transoctenyl)-5-oxo-1alpha-cyclopentyl]cis-5-heptenoicacid was the active ingredient.

EXAMPLE 110

A capsule was prepared by the procedure of Example 108 except that7-[3alpha-methyl-5-oxo-2beta-(3alpha-hydroxy-4-fluoro-1-trans-octenyl)-1-alpha-cyclopentyl]-cis-5-heptenoicacid methyl ester was the active ingredient.

EXAMPLE III

A capsule was prepared by the procedure of Example 109 except thatmethyl7-[2beta-(4,4-dimethyl-3alpha-hydroxy-1-trans-octenyl)-5-oxo-1alpha-cyclopentyl]cis-5-heptenoatewas the active ingredient.

EXAMPLE 112

A tablet was found containing:

    ______________________________________                                                               Per Tablet                                             ______________________________________                                        7-[3 alpha-methyl-5-oxo-2 beta-(3 alpha-                                                               25      mg.                                          hydroxy-4-fluoro-1-trans-octenyl)-                                            1 alpha-cyclopentyl]-cis-5-heptenoic                                          acid                                                                          Dicalcium Phosphate Dihydrate, Unmilled                                                                175     mg.                                          Corn Starch              24      mg.                                          Magnesium Stearate       1       mg.                                          TOTAL Weight             225     mg.                                          ______________________________________                                    

The7-[3-alpha-methyl-5-oxo-2beta-(3alpha-hydroxy-4-fluoro-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoicacid and corn starch were mixed together and passed through a #00 screenin Model "J" Fitzmill with hammers forward. This premix was then mixedwith dicalcium phosphate and one-half of the magnesium stearate, passedthrough a #1A screen in Model "J" Fitzmill with knives forward, andslugged. The slugs were passed through a #2A plate in a Model "D"Fitzmill at slow speed with knives forward, and the remaining magnesiumstearate was added. The mixture was mixed and compressed.

EXAMPLE 113

A tablet was formulated in the same manner as in Example 112 except that7-[2beta-(4,4-dimethyl-3-alpha-hydroxy-1-trans-octenyl)-5-oxo-1alpha-cyclopentyl]cis-5-heptenoicacid was the active ingredient.

EXAMPLE 114

A tablet was formulated in the same manner as in Example 112 except that7-[3alpha-methyl-5-oxo-2beta-(3alpha-hydroxy-4-fluoro-1-trans-octenyl)-1alpha-cyclopentyl]-cis-5-heptenoicacid methyl ester was the active ingredient.

EXAMPLE 115

A tablet was formulated in the same manner as in Example 112 except thatmethyl7-[2beta-(4,4-dimethyl-3alpha-hydroxy-1-trans-octenyl)-5-oxo-1alpha-cyclopentyl]-cis-5-heptenoatewas the active ingredient.

We claim:
 1. A composition of matter comprising a compound of theformula: ##STR55## wherein R is hydrogen or lower alkyl; R₆ is hydrogenor lower alkanoyl, tetrahydropyranyl, benzoyl, trialkylsilyl, benzyl,benzhydryl, trityl; and R₉ is hydrogen or lower alkyl or enantiomers orracemates thereof.
 2. The composition of claim 1 wherein R₆ is hydrogen.3. The composition of claim 2 wherein said compound is7[5-oxo-2beta(3-alpha-hydroxy-4-fluoro-4-methyl-1-trans-octenyl)-1-alpha-cyclopentyl]-cis-5-heptenoicacid.
 4. The composition of claim 2 wherein said compound is7[5-oxo-2beta(3alpha-hydroxy-4-fluoro-1-trans-octenyl)-1-alpha-cyclopentyl]-cis-5-heptenoicacid.